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Curr GenetDOI 10.1007/s00294-014-0467-5

RESEARCH ARTICLE

Damage response involves mechanisms conserved across plants, animals and fungi

M. A. Hernández‑Oñate · A. Herrera‑Estrella

Received: 30 August 2014 / Revised: 10 December 2014 / Accepted: 18 December 2014 © Springer-Verlag Berlin Heidelberg 2015

pathways, suggesting evolutionary conservation across the three kingdoms.

Keywords Injury response · Extracellular ATP (eATP) · Conidiation · Reactive oxygen species (ROS) · Mitogen-activated protein kinase (MAPK) · Calcium

AbbreviationsROS Reactive oxygen speciesFIS Fruiting inducing substancesNox NADPH oxidaseMAPK Mitogen-activated protein kinaseJA Jasmonic acidEGTA Ethylene glycol tetraacetic acid (extracellular

Ca2+ chelating agent)PRR Pattern recognition receptorsPAMP Pathogen-associated molecular patternsDAMP Damage-associated molecular patternseATP Extracellular ATPPGE ProstaglandinsPO PhenoloxidaseJNK c-Jun N-terminal kinaseWB Woronin bodySO SOFT proteinCDPK Calcium-dependent protein kinasesCAMK Ca2+/calmodulin-dependent kinaseCRZ Calcineurin-responsive zinc finger transcription

factorH2O2 Hydrogen peroxideSIPK Salicylic acid-induced protein kinaseWIPK Wound-induced protein kinaseERK Extracellular signal-regulated kinaseMeJA Methyl jasmonatePCD Programed cell deathα-Dox α-Dioxygenase

Abstract All organisms are constantly exposed to adverse environmental conditions including mechanical damage, which may alter various physiological aspects of growth, development and reproduction. In plant and animal systems, the damage response mechanism has been widely studied. Both systems posses a conserved and sophisticated mechanism that in general is aimed at repairing and pre-venting future damage, and causes dramatic changes in their transcriptomes, proteomes, and metabolomes. These damage-induced changes are mediated by elaborate sign-aling networks, which include receptors/sensors, calcium (Ca2+) influx, ATP release, kinase cascades, reactive oxy-gen species (ROS), and oxylipin signaling pathways. In contrast, our current knowledge of how fungi respond to injury is limited, even though various reports indicate that mechanical damage triggers reproductive processes. In fungi, the damage response mechanism has been studied more in depth in Trichoderma atroviride. Interestingly, these studies indicate that the mechanical damage response involves ROS, Ca2+, kinase cascades, and lipid signal-ing pathways. Here we compare the response to mechani-cal damage in plants, animals and fungi and provide evi-dence that they appear to share signaling molecules and

Communicated by D. E. N. Rangel.

This article is part of the Special Issue “Fungal Stress Responses”.

M. A. Hernández-Oñate · A. Herrera-Estrella (*) Laboratorio Nacional de Genómica para la Biodiversidad, CINVESTAV-Irapuato, 36821 Irapuato, GTO, Méxicoe-mail: aherrera@langebio.cinvestav.mx

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Introduction

All organisms are continuously exposed to adverse envi-ronmental conditions including, among others, desicca-tion, extreme temperatures, high light intensities, ultravio-let radiation, heavy metals and mechanical damage, which affect their growth, development and reproduction (Potters et al. 2007). Using different strategies they adapt to these conditions, and although the responses vary, the goal is invariably to survive to the adverse condition. In this sense, plants and animals rely on tissue integrity for multiple vital processes such as maintaining homeostasis, and cell to cell communication to avoid desiccation and infection (Heil et al. 2012). Plants, as sessile organisms cannot escape from injuries caused by chewing insects or larger herbi-vores, whereas animals are exposed to mechanical dam-age and injuries mainly caused by predators. Consequently, they have developed adequate mechanisms to rapidly and reliably respond to mechanical damage. The mechanical damage response mechanism has been widely studied in plants and animals; various reports indicate that they share a mechanism that involves the production of reactive oxy-gen species (ROS), calcium signaling and lipid metabolism,

which are essential for the response (Aguirre and Lambeth 2010; Arimura and Maffei 2010; Jaffe 2010; Jiang et al. 2011; León et al. 2001; Mittler et al. 2011).

On the other hand, organisms such as fungi, which com-prise one of the three main eukaryotic kingdoms, are excel-lent models to study environmental sensing because of their simple, but evolutionarily conserved, signal-transduction pathways that are often equivalent to those present in mul-ticellular eukaryotic organisms (Bahn et al. 2007). Due to their immobility, multicellular (filamentous) fungi are prey to a variety of animal predators and parasites including fun-givorous nematodes and insects, and are therefore constantly exposed to mechanical damage. Nevertheless, our current knowledge of how fungi respond to injury is limited; the few existent reports go back to the 1960’s, 1970’s or even earlier, with only a few exceptions. The fungi in which the response to injury has been studied to some extent are the basidiomy-cetes Schizophyllum commune and Sclerotium rolfsii, the glomeromycete Glomus intraradices and the ascomycetes Trichoderma atroviride, Aspergillus spp., and Neurospora crassa. In S. commune, mechanical damages results in the production of fruiting bodies in the damaged area (Fig. 1a, panel I; Leonard and Dick 1968; Leonard and Raper 1969;

Fig. 1 Formation of reproductive structures in response to injury. a I S. commune fruiting body formation triggered by release of FIS after hyphae lysis, arrow shows the contact zone with FIS (Leonard and Dick 1968). II Conidiation induced by mechanical damage in A. flavus (photograph kindly provided by Dr. Anna Calvo). III–VI Pho-tograph showing the conidiation in the injury area in III T. atrovir-ide (Hernández-Oñate et al. 2012), IV T. harzianum, V T. hamatum,

VI T. virens 29.8. III–VI Photographs were taken 48 h after hyphal damaged. IV–VI (Hernández-Oñate et al. unpublished data). b Illus-tration of the regeneration and conidiation processes of T. atroviride after injury. After injury extracellular ATP (eATP) is released, which triggers the injury response. ROS, oxylipins and calcium play an important role in cell differentiation during conidiophore formation in response to injury (redrawn and modified from Steyaert et al. 2013)

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Leonard and Dick 1973). In the case of Sclerotium rolf-sii, mechanical damage induces sclerotia formation (Henis et al. 1965), and in Aspergillus flavus it triggers production asexual reproduction structures (conidia) (Fig. 1a, panel II). Recently, studies of the response to injury have contributed morphological and biochemical data to aid in the understand-ing of the response mechanism of fungi. Fester and Hause (2005) showed that in Glomus intraradices mechanical dam-age provokes accumulation of ROS. In Aspergillus spp., and N. crassa, it was demonstrated that the damaged hyphae are sealed through the formation of the Woronin body (WB) at the septal pore adjacent to the damaged cell, thereby pre-venting excessive loss of cytoplasmic content and cell death. Subsequently, one or more hyphal tips are formed from the sealed hyphae, resulting in the resumption of growth and reconnection of hyphae (Figs. 1b, 2; Jedd 2011).

Similarly to what has been observed in S. commune and S. rolfsii, in Trichoderma atroviride it has been demonstrated that mycelial injury induces the formation of conidia in the damaged area (Fig. 1a, panel III; Casas-Flores et al. 2004; Hernández-Oñate et al. 2012). Likewise, T. harzianum, T. hamatum and T. virens also produce conidia in response to

injury (Fig. 1a, panels IV–VI; Hernández-Oñate et al. unpub-lished data). Interestingly, high-throughput RNA-seq analy-ses of the response of T. atroviride to injury suggested an oxidative response and activation of calcium-signaling path-ways, as well as the participation of lipid metabolism, in this phenomenon. Subsequent biochemical and gene replacement experiments demonstrated that injury triggers ROS produc-tion in the damaged area and that NADPH oxidase activity is essential for this production and for asexual development in response to damage. Moreover, the analyses also pro-vided evidence of H2O2 and oxylipin production that, as in plants and animals, may act as signal molecules in response to injury (Hernández-Oñate et al. 2012). These results sug-gested that the injury response of T. atroviride involves sign-aling pathways sharing common features with the response to injury of animals and plants. Here, we discuss the simi-larities between the response to injury of plants, animals and fungi. We also propose the use of filamentous fungi as models to accelerate the pace with which we make discover-ies leading to a deeper understanding of the response mecha-nism to injury, which could be useful to better understand the injury healing and transplantation processes.

Fig. 2 Appearance and distribution of Woronin bodies in A. nidu-lans, N. crassa and S. commune. I Woronin bodies (arrowheads) at the A. nidulans septal pore (sub-apical region of hypha). Bar 250 nm (Momany et al. 2002; reprinted with permission from Mycologia. ©The Mycological Society of America). II Septal pore cap (arrow-heads) of S. commune on either side of the dolipore septum. Bar 250 nm (Müller et al. 1998; reprinted with permission from the Soci-ety for General Microbiology). III Morphology of refractive HEX-1 crystals. Bars 5 μm (Tey et al. 2005). I, II and III show transmission electron micrographs. IV Growth of N. crassa after cells was lysed

by cutting. Arrow indicates a Woronin body that has occluded the septal pore. Scale bar 10 μM (Jedd and Chua 2000). V SOFT-GFP localizes to septal plugs in injured hyphae in N. crassa (arrowhead). Hyphae were cut with a razor blade and immediately analyzed by fluorescence microscopy. (Fleiβner and Glass 2007). VI Regenera-tion of damaged hyphae in N. crassa 30 min after injury, white arrow indicates SOFT-GFP accumulation at the septal pore (Fleiβner and Glass 2007; reproduced with permission from the American Society for Microbiology)

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Injury signals

Reports in plants and animals have shown that tissue disrup-tion is readily sensed and subsequently leads to rapid and adequate responses such as sealing the injury, healing of the damaged tissue and a local or systemic resistance induc-tion to prevent infection of the temporarily unprotected tis-sues (Heil et al. 2012; Nam et al. 2012). In plants, the first response is the production of molecules that function as cues of damage and the perception of these signals triggers the injury response. These signals include the oligopeptide systemin (so far identified only in Solanaceae) and oligo-saccharides released by damage to the cell wall, which can trigger a response mediated by jasmonic acid (JA, reviewed by León et al. 2001). In general, many JA-inducing elicitors are plant-derived molecules or fragments released that do not occur in the extracellular space of an intact plant tissue (for review see Heil 2009). Recently, Heil (2012) reported that defense-related responses, including the synthesis of the wound hormone JA, in plants can be elicited by several endogenous molecules when these are applied exogenously. They applied aqueous solutions of ATP, sucrose or leaf extract to slightly injured leaves of lima bean (Phaseolus lunatus) and observed significant increases in endogenous levels of JA. In the case of the leaf extract and sucrose, they observed significantly greater effects compared to mechani-cal wounding. Moreover, they showed that Arabidopsis thal-iana and tomato also respond to wounding or the application of leaf extracts with strong increases in their endogenous JA content, whereas maize and lima bean exhibited strong responses to extracellular sucrose (Heil 2012). These obser-vations suggested that plants present a “Damaged-self recog-nition” mechanism in response to wounding, in which these elicitors are perceived sufficiently fast to mount an appropri-ate general wound response (for review see Heil 2009, 2012; Heil et al. 2012). Interestingly, the “Damaged-self recogni-tion” mechanism has several similarities to certain aspects of the human immune system. A central component of the human immune system relies on the recognition of microbial molecules such as flagellin, chitin or microbial DNA, via the interaction of these molecules with Toll-like receptors or other pattern recognition receptors (PRRs) to control infec-tions. This strategy is, surprisingly, highly analogous to the mechanisms by which plants recognize pathogen-associated molecular patterns (PAMPs) via PRRs (reviewed by Heil et al. 2012; Takeuchi and Akira 2010). Most authors argue that the appearance of endogenous molecules in the extra-cellular space represents a reliable signal of tissue disrup-tion. Normal cell constituents, or their fragments, that can be released into the extracellular milieu during states of cel-lular stress or damage, function as “stress signals”, “alarm-ins” or “damage-associated molecular patterns” (DAMPs). These include molecules such as ATP or adenosine, RNA or

DNA, or specific proteins, or fragments of proteins, such as histones, cyclophilins or fibrinogen, which cause inflamma-tion and trigger other immune-related processes (Chen and Nuñez 2010; Zeiser et al. 2011). The DAMPs then interact with Toll-like receptors or other PRRs consequently activate multiple components of the human innate immune system (such as the recruitment of neutrophils and macrophages and the production of proinflammatory cytokines and chemokines, reviewed by Heil et al. 2012). The release of ATP is also an important early danger signal in fish (Kawate et al. 2009) and algae (Torres et al. 2008). In humans, the perception of extracellular ATP (eATP) by purinergic recep-tors is one of the main biological mechanisms responsible for epithelial intracellular calcium mobilization (Kurashima et al. 2012; Sherwood et al. 2011). In zebrafish, the ATP that is released after an injury is sensed by a purinergic P2Y receptor, which in turn modulates NADPH oxidase (Dual oxidase Duox1) (De Oliveira et al. 2014).

Information obtained in the last past few years indi-cates that injury signal molecules and their perception are highly similar between plants and animals, so it is con-ceivable that these mechanisms may also be conserved in fungi. In this sense, Leonard and Dick (1968) showed that lysis of S. commune mycelium causes the release of sub-stances which when brought into contact with undamaged mycelia are capable of inducing the formation of fruiting bodies (Basidiomycetes reproduction structures). These substances were called fruiting-inducing (FIS; see Fig. 1a, panel I). Several attempts were made to determine the nature of such substances, and found that treatments with proteases, RNases and DNases did lead to a significant reduction in the activity of FIS. However, upon fractiona-tion of the lysate, fractions having FIS activity showed maximum absorption at a 263 nm wavelength (Rusmin and Leonard 1978), which suggests that those substances could be related to nucleotides, which absorb at a similar wavelength. The mechanism by which FIS activates devel-opment in S. commune was suggested to be through the activation of phenoloxidases, which are related to fruiting (Phillips and Leonard 1976). However, this has not been demonstrated. Although, the nature of FIS and the mecha-nism by which they activate fruiting bodies formation in S. commune are still unknown, they opened and avenue to think that a damaged-self recognition also exists in fungi. Accordingly, we proposed that upon mycelial injury T. atroviride releases substances that are perceived through a transmembrane receptor to trigger the injury response (see Fig. 3; Hernández-Oñate et al. 2012). Recently, Medina-Castellanos et al. (2014) showed that exposure of T. atroviride mycelium to extracellular ATP induces the formation of asexual reproduction structures. Moreo-ver, the application of apyrase (an enzyme that hydrolyzes extracellular ATP) and an extracellular Ca2+ chelating

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agent (EGTA) to colonies that were damaged with a scal-pel resulted in strongly reduced conidiation in the wound region (96 and 98 %, respectively), as compared with the injured control. These observations indicated that extracel-lular ATP plays a major role in the injury response, and could act as cue or DAMP to trigger asexual development (Medina-Castellanos et al. 2014).

It is evident that upon injury T. atroviride also releases substances that are required for the injury response. How-ever, the need to design experiments to elucidate through which receptors they are perceived is evident. In sum-mary, it appears that the similarities between damaged-self recognition in animals and plants can help us design the experiments to understand how fungi perceive mechanical damage.

Injury healing and regeneration

The ability to respond to injury and healing tissue is a fun-damental property of all multicellular organisms; injury

breaks the outer protective layers of an organism or organ, and the injured tissue is therefore prone to desiccation and infection. Thus, injury requires several counter-measures, and many of these are independent of the causal agent (Bostock and Stermer 1989; reviewed by Gurtner et al. 2008).

In plants, counter-measures that are taken by plants upon tissue disruption include wound periderm formation, lignification of the cell walls and deposition of phenolic compounds. The impervious tissues that are formed in this context resist water loss as well as penetration by most pathogens and are also less valuable food sources for her-bivores (reviewed by Heil et al. 2012). Several reports indi-cate that the production of ROS is essential for the response to injury, and important to induce repair mechanisms in the damage zone (Heil et al. 2012; Mittler et al. 2011). ROS signaling induces multiple general resistance responses that involve DNA repair, programmed cell death, cell wall thickening, and the accumulation of phenolic compounds (Leitner et al. 2005; Mittler et al. 2011). Additionally, the lipoxygenase pathway plays an important role in the

Fig. 3 Schematic representation of the events occurring during the response to injury in T. atroviride. Injury provokes the release of DAMPs (eATP) and Ca2+. eATP is then recognized by a G protein-coupled receptor (GPCR) type hypothetical receptor. Perception of eATP and changes in intracellular calcium levels provoke activation of the NADPH oxidase 1 complex (Nox1), which regulates ROS production. MAPK (Tmk1 and Tmk3) signaling pathways are acti-vated in response to injury, the Tmk3 pathway is activated by Nox1 dependent ROS production and eATP, whereas the Tmk1 pathway is activated only by eATP. Oxylipin synthesis is induced after injury, which could play role in cell differentiation. DAMP damage-associ-ated molecular patterns, eATP extracellular ATP, α, β, and γ subunits

of a heterotrimeric G protein, Dox dioxygenases, Lox lipoxygenase, FA fatty acid, SOD superoxide dismutase, Vm membrane potential, WB Woronin body, SO SOFT protein, PCD programed cell death, CAMK Ca2+/calmodulin-dependent kinase, Crz1 calcineurin-respon-sive zinc finger transcription factor, CR calcium response. Solid arrows indicate data supported by experimental evidence in Tricho-derma, discontinuous arrows indicate data experimentally supported in other fungal systems, and dotted arrows indicate completely hypo-thetical steps. Black arrows indicate the signaling mechanisms and molecular components shared across the three kingdoms and red arrows, the fungal specific events

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injury response and healing (Noordermeer et al. 2001). In potato tubers injury healing is critical to avoid infection by Erwinia carotovora subsp. carotovora (causal agent of bac-terial soft rot) and Fusarium sambucinum (causal agent of fungal dry rot). In this case, the deposition of suberin com-ponents (phenolic and aliphatic domains) in the injury zone is responsible for the final resistance to infection (Lulai and Corsini 1998). In animals, depending on the nature of the injury, repair mechanisms are initiated immediately fol-lowing the insult and include activation and recruitment of macrophages and neutrophils. Then, the localized stem cells become activated, and growth factors (TGF-α, KGF, HGF), cytokines, interleukins (IL-1β, IL-2, IL-4, IL-13), matrix materials (fibronectin, collagen, laminin), and pros-taglandins (PGE2) are released, and activation of the coagu-lation cascade takes place. Subsequently, cells adjacent to the site of injury secrete extracellular matrix through integrin and growth factor signaling, the cytoskeleton is reorganized to facilitate movement to close the injury and reestablish the intact barrier function (reviewed by Gailit and Clark 1994; Crosby and Waters 2010; Gurtner et al. 2008; Martin and Leibovich 2005). Work using zebrafish revealed a novel mechanism of early leukocyte recruit-ment to the injury site through a concentration gradient of hydrogen peroxide (Yoo and Huttenlocher 2009). Moreo-ver, in Drosophila, local wounds in the integument rapidly induce activation of a novel circulating hemolymph serine protease, Hayan, which in turn converts pro-phenoloxidase to phenoloxidase (PO), an active form of melanin-forming enzyme. The Hemolymph Hayan-PO cascade is required for redox-dependent activation of the c-Jun N-terminal kinase (JNK)-dependent cytoprotective program in neu-ronal tissues, thereby achieving organism level of homeo-stasis to resist local physical trauma (Nam et al. 2012). The process of injury repair outlined above is complex, involv-ing interactions between multiple initiation factors, soluble ligands, structural elements, and the mechanical environ-ment. These processes are finely regulated by several key signaling pathways, including sonic hedgehog (extensively activated during repair of the airway epithelium; Watkins et al. 2003), Rho GTPases (regulate cytoskeletal remode-ling and cell contraction, reviewed by Crosby and Waters 2010), and MAP kinase pathways (regulate cell prolif-eration, differentiation, and cell migration). White et al. (2005) showed that migration of airway epithelial cells was decreased when cells were treated with inhibitors of p38 MAPK, JNK, or ERK1/2, and that both p38 and JNK were rapidly activated in cells near the wound edge, and Wnt/β-catenin signaling the role of β-catenin-mediated wing-less integration (Wnt) signaling is proven to be central to mechanisms of injury healing in fibrosis, cancer, and stem cell maintenance (reviewed by Crosby and Waters 2010). In Xenopus oocytes during injury repair, the reorganization

of microtubules and injury closure were dependent on Rho GTPases and extracellular calcium (Bement et al. 1999; Clark et al. 2009). Then, during progression of the injury repair process, these localized progenitor cells, as well as newly recruited circulating progenitor cells, proliferate and undergo phenotypic differentiation to reestablish the integrity and functional organization of the epithelial layer (reviewed by Gailit and Clark 1994; Crosby and Waters 2010; Gurtner et al. 2008; Martin and Leibovich 2005).

Since septated fungi grow through hyphae, which are interconnected by septal pores through which there is a constant flow of protoplasm (Cole 1986), when hyphae are damaged, an “organelle” known as the Woronin body (WB) is directed toward the septal pore for sealing the damaged hyphae, to thereby prevent both excessive loss of cytoplasmic contents and cell death (see Fig. 2; Jedd 2011; Markham 1994; Maruyama et al. 2005; Tey et al. 2005). Initially, the septal pore cap (SPC), a structure equivalent to Woronin bodies was described in the Basidiomycetes fungi, this structure has also been localized in the septal pore; the shape of this structure has morphological differences depending on the fungal species (Fig. 2, panel II; Markham 1994; Müller et al. 1998). Reports in N. crassa indicate that the Hex-1 protein represents the major proportion of the Woronin bodies (Tenney et al. 2000), and it has been shown that the Hex-1 is assembled forming a hexagonal structure, resulting in the formation of the Woronin body, which also has hexagonal shape (Fig. 2, panel III; Jedd and Chua 2000; Yuan et al. 2003). Subsequent studies indicated that the WB shares the biogenesis with peroxisomes, where the Woronin sorting complex protein plays an important role (Liu et al. 2008, 2011). The mechanism for sealing of damaged hyphae is apparently regulated in at least two lev-els: a transcriptional level and a post-transcriptional level. Analysis of the expression of hex-1 in Trichoderma reesei showed two transcripts (product of alternative splicing) strongly expressed in early stages of growth (Curach et al. 2004). Accordingly, expression analyses of hex-1 in N. crassa and Aspergillus nidulans also showed the presence of two transcripts present along the hyphae with a tendency to be polarized, as both transcripts are highly enriched in the apical part of hyphae. Nevertheless, no increases were detected in hex-1 gene expression in response to mechani-cal damage (Maruyama et al. 2005; Tey et al. 2005), sug-gesting that its expression is not influenced by this stimu-lus. At the post-transcriptional level, Juvvadi et al. (2007) determined that protein kinase C activity (PKC) is impor-tant for the multimerization of Hex-1 and the correct locali-zation of the WB at the septal pore. Recently, other pro-teins have been associated with sealing of the septal pore in response to cell lysis, such as SOFT (SO) that is also involved in sealing of the septum but independently of Hex-1 (Fleiβner and Glass 2007; Maruyama et al. 2005).

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Positioning of SO at the septal pore after damage is imme-diate (Fig. 2V, VI). In 2007 Fleiβner and Glass showed that this mobilization takes place in the first 16 s after hyphal lysis. Additionally, in Aspergillus oryzae, SO accumulates at the septal pore in response to various stresses, includ-ing low and high temperature, pH changes and nutritional stress (Maruyama et al. 2005). The WB has also been linked to various stress types, such as cell death that occurs during heterokaryon incompatibility (Fleiβner and Glass 2007). Interestingly, gene replacement mutants of the hex-1 gene showed that it is essential for the regeneration of the damaged hyphae (Jedd 2011; Tey et al. 2005).

Regeneration of damaged cells has been extensively studied in animals and plants, obtaining the greatest advances in injury regeneration in animals. The study of injury has had important implications in medicine. In this sense, studies in reptiles and amphibians have permitted important advances in our understanding of tissue regen-eration and healing (Chang et al. 2009). Although the regeneration phenomenon has been target of several studies in recent years, mainly in animals, fungi have been poorly studied. In this regard, reports to date show that after septal pore sealing, one or more hyphae are formed, resulting in the regeneration and reinitiation of growth of the damaged hyphae, which then merge with other hyphae (see Figs.1b, 2, panels IV, VI; reviewed by Jedd 2011; Fleiβner and Glass 2007). However, data on the regulation of regeneration were not reported in those studies. Recently, we reported a high-throughput RNA-seq analysis of the response to injury in T. atroviride, which indicated that at least 25 genes related to cytoskeleton organization, DNA replication and cell cycle, which in plants are important for regeneration of damaged tissue, are up-regulated in response to the insult in Trichoderma. Within this group of genes, a homologue of the yeast sda1 gene was found (Hernández-Oñate et al. 2012). In yeast, this gene plays a critical role in the reset-ting of the cell cycle (Zimmerman and Kellogg 2001). This information suggested that as in plants and animals, in T. atroviride reorganization of the cytoskeleton and cell cycle resetting are also required for injury healing and regenera-tion of damaged hyphae.

Signaling pathways involved

Mechanical damage provokes a series of molecular events in plants and animals, which transduce the alarm signals and eventually result in the accumulation of metabolites required for the damage response. In plants and animals the damage response has been widely studied. Although the regulatory mechanisms involved in the response are not yet fully understood, many molecules have been identified as nodes of complex regulatory networks that enable plants

to optimize energy and resource allocation, and deploy appropriate defenses. In this context, two questions arise when analyzing the mechanisms that regulate the damage response in fungi: (1) What sort of molecules and regula-tory mechanisms do fungi use to respond to mechani-cal damage? (2) Are these mechanisms also conserved in plants and animals? Recent reports have allowed us to get closer to answering these questions. Below, we describe the principal signaling pathways involved in the mechanical damage response in plants, animals and fungi, highlighting the similarities between the kingdoms.

Calcium signaling

Calcium has been recognized as an important second messenger involved in numerous signaling actions in all eukaryotes. Ca2+ influx, which changes cytosolic Ca2+ concentration, is often involved in stress responses and developmental regulation. Together with fluxes of other ions, fluxes of Ca2+ ions usually result in temporary changes of cell membrane potentials (reviewed by Wu and Baldwin 2010). Reports in plants and animals indicate that after perception of mechanical damage Ca2+ channels are activated, resulting in a Ca2+ influx in the damage zones and changes in intracellular calcium levels (Arimura and Maffei 2010; Braam 1992; Jaffe 2010; Jiang et al. 2011; Maffei et al. 2004). These changes are further translated into downstream actions through calcium signaling, which include various Ca2+ sensor proteins, calmodulins, calmo-dulin-binding proteins, calcium-dependent protein kinases (CDPKs), other EF-hand motif proteins containing Ca2+-binding proteins, and Ca2+-binding proteins without EF-hands. Furthermore, Ca2+ is associated with ROS and nitric oxide production in plants (review by Wu and Baldwin 2010; Arimura and Maffei 2010; Braam 1992; Jaffe 2010; Jian et al. 2011).

In fungi, calcium also has a function as second mes-senger during growth, development and cell differentiation (reviewed by Steyaert et al. 2010; Roncal and Ugalde 2003). Interestingly, Nelson et al. (2004) showed that mechanical perturbation provokes a transient increase in intracellular calcium in Aspergillus awamori. In full agreement with these reports and similarly to what has been observed in plants and animals, in T. atroviride using RNA-seq analysis our laboratory reported a series of induced genes involved in calcium signaling and transport early after injury. This set of genes includes calcium transporters, phospholipase C, a Ca2+/calmodulin-dependent kinase-1 (CAMK-1) and a Calcineurin-responsive zinc finger transcription factor (crz1), all of them considered key components in calcium signaling in response to different types of stress, suggest-ing that in the early steps of injury response an increase in cytoplasmic Ca2+ is necessary and that calcium signaling

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plays an important role in the injury response (Hernández-Oñate et al. 2012). Moreover, Medina-Castellanos et al. (2014) demonstrated that in T. atroviride extracellular Ca2+ induces the formation of asexual reproduction structures and that the extracellular Ca2+ chelating agent (EGTA) reduces conidiation in the wound region. These data sug-gest that calcium signaling plays an important role in the injury response in T. atroviride (Fig. 3).

ROS signaling

All aerobic organisms generate reactive oxygen species (ROS) as an inevitable product of metabolism. Superox-ide anion (O2

−), hydrogen peroxide (H2O2), singlet oxygen (1O2), and hydroxyl radical (OH) are collectively called ROS; they are produced in mitochondria (primarily through respiration), chloroplasts, and peroxisomes, as well as on the external surfaces of plasma membranes (Aguirre et al. 2005, 2006; Zorov et al. 2005). ROS may affect cellular compo-nents, by oxidation of proteins, DNA, lipids and other bio-molecules potentially impacting cell viability (Aguirre et al. 1989; Leiter et al. 2005; McCord 2000). However, ROS also play important roles in other processes, including cell proliferation, signal transduction, ion transport, cell differ-entiation, plant-pathogen interactions, and injury response (Aguirre et al. 2005; Lamb and Dixon 1997). In plants and animals, several reports indicated that an important response to wounding is the generation of ROS in the damaged area. ROS production can be local and systemic, and mainly dependent on plasma membrane-bound NADPH oxidases (Nox; Aguirre and Lambeth 2010; Arimura and Maffei 2010; Braam 1992; Das and Maulik 2004; Wu and Baldwin 2010).

In plants ROS production reaches a peak of superoxide minutes after injury and 4–6 h maximum H2O2 levels are observed, to later decay. This time course of events sug-gests that H2O2 plays a role as second messenger and signal propagation (Aguirre and Lambeth 2010; Das and Maulik 2004; Leon et al. 2001; Schilmiller and Howe 2005).

In Arabidopsis, two Nox genes, AtrbohD and AtrbohF, are required for pathogen-induced ROS production (Miller et al. 2009; Torres et al. 2002). Further, genetic and phar-macological evidences indicated that NADPH oxidase is involved in wounding-induced ROS production in tomato plants (Miller et al. 2009; Orozco-Cardenas et al. 2001; Orozco-Cardenas and Ryan 1999; Sagi et al. 2004). Inter-estingly, there is a complex relationship between ROS and Ca2+ influxes, where Ca2+ appears to participate both upstream and downstream of ROS. There are reports that indicated that Ca2+ influxes usually result in tem-porary changes of cell membrane potentials, and activa-tion of NADPH oxidase (reviewed by Wu and Baldwin 2010; Arimura and Maffei 2010; Braam 1992). In addi-tion, in potato plants, Ca2+ binding and phosphorylation

by CDPKs enhance the activity of NADPH oxidase, and lead to the production of ROS (Kobayashi et al. 2007). In Nicotiana benthamiana, the MAPK salicylic acid-induced protein kinase (SIPK) transcriptionally regulates Nox (Asai et al. 2008). Although Nox was originally linked to the immune response upon exposure to pathogens, Sasaki et al. (2009) reported that the production of ROS through Nox is essential for the differentiation of mouse macrophage cells. In zebrafish, the formation of a H2O2 gradient in the injury zone may not only serve to sterilize the wound area, but also plays a role as chemo-attractant for neutrophils, sug-gesting that as in plants, hydrogen peroxide acts as a propa-gation signal in animals (Aguirre and Lambeth 2010; Yoo and Huttenlocher 2009).

In this context, in T. atroviride, we showed that tran-scriptional responses to injury are consistent with the generation of oxidative stress. At least 60 genes encoding proteins related to redox reactions are regulated by injury. These include 16 genes encoding ROS scavenging proteins that are strongly repressed at short times after injury, which levels begin increasing later, to finally recover their original level or reach even higher levels, indicating that the cell ini-tially allows the generation of oxidative stress upon injury (Hernández-Oñate et al. 2012). In total agreement with these observations, pharmacological and genetic analy-ses allowed to demonstrate the cytoplasmic accumulation of ROS in damaged hyphae of both G. intraradices and T. atroviride (Fester and Hause 2005; Hernández-Oñate et al. 2012). Interestingly, as it occurs in plants and animals, we demonstrated that ROS production in the damage zone is also Nox-dependent, likewise, we showed the production of H2O2 in cells adjacent to the injury, suggesting that ROS produced by Nox may also function as propagation of the signal (Fig. 3; Hernández-Oñate et al. 2012). In fungi, ROS production by Nox plays important roles, including regula-tion of cellular functions, ion transport, signal transduction and cell differentiation (for review see Aguirre et al. 2005; Aguirre and Lambeth 2010). Phylogenetic analysis of nox genes indicated that fungi have one, two or three genes (noxA, noxB, noxC) (Takemoto et al. 2007). Additionally, in the genome of various fungi noxR genes encoding the regulatory subunit of Nox activity are found (Takemoto et al. 2006, 2007, 2011). Interestingly, in full agreement with the idea of extracellular ATP acting as a cue or DAMP, Medina-Castellanos et al. (2014) showed that eATP stimu-lates Nox1-dependent formation of ROS in T. atroviride, suggesting that Nox1 acts downstream of the perception of eATP (Fig. 3).

MAPK signaling

The MAPK is a well-conserved signaling pathway that reg-ulates various cellular processes in all eukaryotes. The role

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of MAPK signaling in response to mechanical damage has been studied in more detail in plants; especially in Nicoti-ana spp. and in Arabidopsis, and many studies have shown the critical role of MAPKs in this process. Wu et al. (2007) demonstrated that SIPK and the wound-induced protein kinase (WIPK) play a central role in plant responses to herbivory and wounding. Herbivory and wounding elicit MAPK activity (for review see Wu and Baldwin 2010; Dombrowski et al. 2011; León et al. 2001; Taj et al. 2010). SIPK also regulates herbivory-induced ethylene biosyn-thesis in N. attenuata (Wu et al. 2007). A link between the Ca2+ influxes and MAPK signaling has been suggested, since overexpressing a voltage-gated Ca2+ channel in rice enhances elicitor-induced MAPK activity (Kurusu et al. 2005). In tobacco cell suspension cultures, the application of lanthanum chloride and calmodulin antagonists, inhibit the pathogen elicitor-elicited MAPK activation (Romeis et al. 1999). However, this interaction between herbivory-induced kinase signaling, especially MAPK signaling, and Ca2+ influxes is not yet clear (reviewed by Wu and Bald-win 2010). In animals, the participation of MAPK signal-ing in the injury response was also demonstrated recently. The involvement of a MAPK pathway in the response to brain and nerve sciatic injury was demonstrated (Chang et al. 2010; Li et al. 2013; Medders and Kaul 2011; Taj et al. 2010). Further, Bachstetter et al. (2013) demon-strated, using an in vitro model, that the MAPK p38α regu-lates microglial responsiveness to diffuse traumatic brain injury. Moreover, phosphorylation of the transcription factor Grainy Head by ERK is important for tissue regen-eration and healing in Drosophila melanogaster (Kim and McGinnis 2011; Rämet et al. 2002), and the activation of ERK is required in mammalian cells for both, restoration of damaged tubular epithelial cells and inhibition of fibro-sis progression following injury (Jang et al. 2013). In addi-tion, Ca2+ flux and phosphorylation of MAPK play impor-tant roles in the systemic inflammatory response syndrome caused by injury (Zhang et al. 2010).

In fungi, MAPK signaling pathways have been linked to signal transduction in response to oxidative stress, osmotic stress, cell proliferation and differentiation (reviewed by Jendretzki et al. 2011; Aguirre et al. 2006; Chauhan et al. 2006; Hagiwara et al. 2009; Lara-Rojas et al. 2011; Rod-ríguez-Peña et al. 2010). T. atroviride has three MAPKS, namely Tmk1, Tmk2 and Tmk3, which are related to mycoparasitism/filamentous growth, cell wall integrity and osmotic stress response pathways, respectively (Delgado-Jarana et al. 2006; Mendoza-Mendoza et al. 2003; Reith-ner et al. 2007; Zeilinger and Omann 2007). Recently, our laboratory proposed a connection between the MAPK path-way and the response to injury in T. atroviride (Hernán-dez-Oñate et al. 2012). In agreement with this proposal, Medina-Castellanos et al. (2014), using genetic analyses

demonstrated that Tmk1 and Tmk3 are involved in the injury response, since Δtmk1 and Δtmk3 mutant strains exhibited a dramatic decrease in conidia production in response to injury (95 and 80 %, respectively), suggest-ing that transduction of injury-related signals leading to conidiation is modulated mainly by MAPK pathways. Tmk1 is phosphorylated a minute after injury, and remains activated for up to 30 min; whereas Tmk3 exhibited maxi-mum phosphorylation a minute after injury, decreas-ing very rapidly afterwards, suggesting that Tmk1 plays a sustained role, while Tmk3 participates in a rapid and short response. Interestingly, eATP activates the MAPKs Tmk1 and Tmk3, and Tmk3 activation is Nox1-dependent, whereas Tmk1 activation is Nox1-independent (Fig. 3). Furthermore, Tmk1 and Tmk3 were phosphorylated even in the presence of EGTA, indicating that calcium signal-ing takes place through a MAPK-independent pathway. These data indicate that MAPK pathways play conserved roles in the injury response across three kingdoms, and that there are at least three signaling pathways involved in the injury response, two of them regulated by MAPKs and the third one regulated by calcium in T. atroviride (see Fig. 3; Medina-Castellanos et al. 2014).

Oxylipin signaling

Lipid metabolism plays an important role in the mechani-cal damage response of plants and animals (Farmer et al. 2003; Koo et al. 2009; Noverr et al. 2003). After production of ROS and increased intracellular calcium, the production of oxygenated fatty acids is observed in plants (oxylipins) and animals (prostaglandins). In the latter, membrane fatty acids are essential for the response (Farmer et al. 2003; Koo et al. 2009; Noverr et al. 2003).

Many reports indicate that oxylipins are involved in controlling defense gene expression, growth, and fertil-ity throughout the plant kingdom and have been studied extensively in Arabidopsis thaliana (for review see Gfeller et al. 2010). Almost all enzymes involved in the oxylipin biosynthetic pathway have been identified in Arabidop-sis. These enzymes include phospholipase D, phospho-lipase A, and other enzymes localized in chloroplasts and peroxisomes, such as lipoxygenases, allene oxide syn-thase, allene oxide cyclase and 12-oxo-phytodienoic acid, among others (for review see Dhondt et al. 2000; Gfeller et al. 2010; Koo et al. 2009; Wu and Baldwin 2010). The oxylipins include jasmonic acid (JA), which together with its precursors and derivatives, such as 12-oxophytodienoic acid (OPDA), methyl jasmonate (MeJA), and other amino acid derivatives, such as isoleucine jasmonil, are designated jasmonates. Jasmonates are synthesized from α-linolenic acid and are considered central regulators of the response to mechanical damage and herbivory (Arimura et al. 2011;

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Gfeller et al. 2011; Koo and Howe 2009; León et al. 2001). The regulation of JA accumulation and signaling after wounding or herbivory is particularly important for the ability of plants to initiate defense reactions in a timely fashion (Gfeller et al. 2010). In both Nicotiana and tomato plants silencing of SIPK and WIPK impairs the accumula-tion of wounding- or herbivory-induced JA (Kandoth et al. 2007; Seo et al. 2007; Wu et al. 2007). However, activat-ing SIPK and WIPK in Nicotiana tabacum by transiently overexpressing their upstream MAPK kinase MEK2 in a constitutively active form does not elicit JA accumulation, making unclear the mechanism by which MAPKs con-trol JA accumulation (Kim et al. 2003). In animals, injury leads to transient increases in calcium (Jaffe 2010; Jiang et al. 2011), and activation of phospholipase A2, that as in plants, is essential for the biosynthesis of prostaglandins and leukotrienes, which are potent modulators of immune responses, the inflammation process, basic host physiologic processes and repair of damaged tissue (Crosby and Waters 2010; Martin and Leibovich 2005; Noverr et al. 2003; Zhao et al. 2011). The most prevalent prostaglandins in mam-mals are derived from arachidonic acid, and have been divided into many subfamilies, the main ones being the prostanoids, which are products of a cyclooxygenase, and the leukotrienes and hydroxyeicosatetraenoic acid, which are produced by lipoxygenases (Noverr et al. 2003).

Interestingly, in T. atroviride genes related to oxylipin biosynthesis were up-regulated during the injury response (Hernández-Oñate et al. 2012). These genes include one encoding a protein with a Patatin domain closely related to phospholipase A2 (Dhondt et al. 2000). Thus, it could be suggested that in T. atroviride, this protein has phospholipase A2 activity and participates in oxylipin generation. Moreo-ver, the transcriptional analyses showed that genes encoding a lipoxygenase, a cytochrome P450, and a 12-oxophytodien-oate reductase are induced. Conversely, a COP9 signalosome subunit, reported as a negative regulator of the biosynthesis of oxylipins (Tsitsigiannis and Keller 2007), is repressed. Furthermore, a gene encoding a protein with homology to the α-dioxygenase of A. thaliana is also induced in response to injury. In Arabidopsis, this gene is induced by pathogens, salicylic acid, intracellular ROS and is reported to generate 2-OH type oxylipins (Mosblech et al. 2010). These results suggest that T. atroviride produces oxylipins in response to mechanical damage through a set of enzymes shared with the biosynthetic pathway of plants and animals (Fig. 3). In total agreement with these observations, preliminary results show that T. atroviride produces 2-hydroxy oxylipins in response to mechanical damage (Hernández-Oñate et al. unpublished data). Moreover, several studies indicate that lipoperoxides and oxylipins are produced during cell differentiation in fungi (Hegedüs et al. 2011; Noverr et al. 2003; Tsitsigiannis and Keller 2007).

Conclusions and perspectives

The response to mechanical damage has been exten-sively studied in plants and animals, whereas in fungi, the few existing studies were carried out during the 1960s and 1970s with limited mechanistic insights. Recently, however, there have been significant efforts to study the response to mechanical damage in fungi and to elucidate the mechanism involved. In this review, we have described how, despite the use of different strategies to adapt to mechanical damage and survive, the three eukaryotic king-doms share molecular mechanisms and some signaling components. These observations suggest that the response to mechanical damage may be a primitive response that has been maintained through evolution. As described above, plants, animals and fungi use the same signaling mecha-nisms, including eATP as a DAMP, which perception trig-gers the activation of Ca2+ channels that results in Ca2+ influxes, activation of calcium signaling cascades, and ROS production through NADPH oxidase activity. In the three kingdoms MAPK signaling pathways are rapidly activated in response to injury, as well as the biosynthesis of oxy-genated fatty acids, which play pivotal roles in the injury response (see Fig. 3). Furthermore, the three kingdoms have different mechanisms to seal and repair the damaged area, which represent solutions to the same problem. On the other hand, as mentioned above in T. atroviride, T. har-zianum, T. hamatum, T. virens, S. commune, S. rolfsii and A. flavus mechanical damage triggers reproductive pro-cesses. However, there are other fungi such as N. crassa and A. nidulans where this is not observed. Therefore, in fungi like in limb regeneration in some animals, we can divide the response to mechanical damage in at least three stages, the first corresponding to wound healing, the second to regeneration of damaged hyphae, and a third step involv-ing cellular differentiation which leads to the formation of reproductive structures (see Fig. 1). The reasons why this third stage does not occur in all fungi are still unknown.

Nowadays, the study of the response to mechanical damage has become more important not only due to the relevance it has in regenerative medicine and agriculture, but also in organ transplantation. Previously, most efforts were directed only to the study of tissue regeneration in reptiles and amphibians, which after mechanical damage are capable of regenerating damaged tissues, and even lost limbs (Chang et al. 2009), and plant responses to herbivory (Arimura et al. 2011; Heil et al. 2012). However, cur-rent notions in immunology hold that not only pathogen-mediated tissue injury but any injury activates the innate immune system, which defense system responds to patho-gen-induced injury with the creation of infectious inflam-mation, and non-pathogen-induced tissue injury with ‘ster-ile’ tissue inflammation. These observations have led to

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study the response to injury and its impact in transplanta-tion (for review see Land 2013; Land and Messmer 2012).

Although, substantial progress has been made in recent years in understanding the signaling pathways involved in mechanical damage response, there are still many questions that remain unanswered in injury. How do fungi recognize the injury signals (DAMPs)? What are the receptors? How does calcium control the injury response? What is the role of oxylipins in the injury response in fungi? How is cell regen-eration regulated in fungi? However, based on the informa-tion discussed here and due to the fact that fungi are fast growing organisms and easy to handle in the laboratory, we propose the use of the filamentous fungi T. atroviride and the advances in high-throughput sequencing technologies as powerful tools to accelerate progress in the understanding of mechanisms regulating the mechanical damage response, including regeneration and cell differentiation.

Acknowledgments Research related to the main subject of this review is supported by grant FOINS-CONACYT (I0110/193/10FON.INST. -30-10) to A H-E. This review article was supported in part by a grant from São Paulo Research Foundation (FAPESP) of Brazil # 2014/01229-4. The authors wish to thank Dr. Ana Calvo for allowing us to use an unpublished photograph obtained by her research group.

References

Aguirre J, Lambeth DJ (2010) Nox enzymes from fungus to fly to fish and what they tell us about Nox function in mammals. Free Radic Biol Med 49:1342–1353. doi:10.1016/j.freeradbiomed.2010.07.027

Aguirre J, Rodríguez R, Hansberg W (1989) Oxidation of Neuro-spora crassa NADP-specific glutamate dehydrogenase by activated oxygen species. J Bacteriol 171(11):6243–6250 (pii 0021-9193/89/116243-08)

Aguirre J, Rios-Momberg M, Hewitt D, Hansberg W (2005) Reac-tive oxygen species and development in microbial eukaryotes. Trends Microbiol 13(3):111–118. doi:10.1016/j.tim.2005.01.007

Aguirre J, Hansberg W, Navarro R (2006) Fungal responses to reactive oxygen species. Med Mycol 44:5101–5107. doi:10.1080/13693780600900080

Arimura GI, Maffei ME (2010) Calcium and secondary CPK signal-ing in plants in response to herbivore attack. Biochem Biophys Res Commun 400:455–460. doi:10.1016/j.bbrc.2010.08.134

Arimura GI, Ozawa R, Maffei ME (2011) Recent Advances in plant early signaling in response to herbivory. Int J Mol Sci 12:3723–3739. doi:10.3390/ijms12063723

Asai S, Ohta K, Yoshioka H (2008) MAPK signaling regulates nitric oxide and NADPH oxidase-dependent oxidative bursts in Nico-tiana benthamiana. Plant Cell 20(5):1390–1406. doi:10.1105/tpc.107.055855

Bachstetter AD, Rowe RK, Kaneko M, Goulding D, Lifshitz J, Van Eldik LJ (2013) The p38α MAPK regulates microglial responsiveness to diffuse traumatic brain injury. J Neurosci 33(14):6143–6153. doi:10.1523/JNEUROSCI.5399-12.2013

Bahn YS, Xue C, Idnurm A, Rutherford JC, Heitman J, Cardenas ME (2007) Sensing the environment: lessons from fungi. Nat Rev Microbiol 5(1):57–69. doi:10.1038/nrmicro1578

Bement WM, Mandato CA, Kirsch MN (1999) Wound-induced assembly and closure of an actomyosin purse string in Xenopus oocytes. Curr Biol 9(11):579–587. doi:10.1016/S0960-9822(99)80261-9

Bostock RM, Stermer BA (1989) Perspective on wound-healing in resistance to pathogens. Annu Rev Phytopathol 27:343–371. doi:10.1146/annurev.py.27.090189.002015

Braam J (1992) Regulation of expression of calmodulin and calmod-ulin-related genes by environmental stimuli in plants. Cell Cal-cium 13:457–463. doi:10.1016/0143-4160(92)90058-Z

Casas-Flores S, Rios-Momberg M, Bibbins M, Ponce-Noyola P, Her-rera-Estrella A (2004) BLR-1 and BLR-2 are key regulatory elements for photoconidiation and mycelial grown in T. atrovir-ide. Microbiology 150:3561–3569. doi:10.1099/mic.0.27346-0

Chang C, Wu P, Baker RE, Maini PK, Alibardi L, Chuong CM (2009) Reptile scale paradigm: Evo-Devo, pattern formation and regeneration. Int J Dev Biol 53(5–6):813–826. doi:10.1387/ijdb.072556cc

Chang MC, Chen YJ, Lee MY, Lin LD, Wang TM, Chan CP, Tsai YL, Wang CY, Lin BR, Jeng JH (2010) Prostaglandin F2a stimu-lates MEK/ERK signaling but decreases the expression of alka-line phosphatase in dental pulp cells. Int Endod J 43:461–468. doi:10.1111/j.1365-2591.2010.01699.x

Chauhan N, Latge JP, Calderone R (2006) Signalling and oxidant adaptation in Candida albicans and Aspergillus fumigatus. Nat Rev Microbiol 4:435–444. doi:10.1038/nrmicro1426

Chen GY, Nuñez G (2010) Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol 10:826–837. doi:10.1038/nri2873

Clark AG, Miller AL, Vaughan E, Yu HYE, Penkert R, Bement WM (2009) Integration of single and multicellular wound responses. Curr Biol 19(16):1389–1395. doi:10.1016/j.cub.2009.06.044

Cole GT (1986) Models of cell differentiation in conidial fungi. Microbiol Rev 50(2):95–132 (PMCID: PMC373060)

Crosby LM, Waters CM (2010) Epithelial repair mechanisms in the lung. Am J Physiol Lung Cell Mol Physiol 298:715–731. doi:10.1152/ajplung.00361.2009

Curach NC, Te’o Valentino SJ, Gibbs MD, Bergquist PL, Nevalainen KMH (2004) Isolation, characterization and expression of the hex1 gene from Trichoderma reesei. Gene 331:133–140. doi:10.1016/j.gene.2004.02.007

Das DK, Maulik N (2004) Conversion of death signal into survival signal by redox signaling. Biochemistry (Mosc) 69(1):16–24. doi:10.1023/B:BIRY.0000016345.19027.54

De Oliveira S, López-Muñoz A, Candel S, Pelegrín P, Calado A, Mulero V (2014) ATP modulates acute inflammation in vivo through dual oxidase 1-derived H2O2 production and NF-κB activation. J Immunol 192:5710–5719. doi:10.4049/jimmunol.1302902

Delgado-Jarana J, Sousa S, González F, Rey M, Llobell A (2006) The Hog1 controls the hyperosmotic stress response in Tricho-derma harzianum. Microbiology 152:1687–1700. doi:10.1099/mic.0.28729-0

Dhondt S, Geoffroy P, Stelmach BA, Legrand M, Heitz T (2000) Soluble phospholipase A2 activity is induced before oxylipin accumulation in tobacco mosaic virus-infected tobacco leaves and is contributed by patatin-like enzymes. Plant J 23:431–440. doi:10.1046/j.1365-313x.2000.00802.x

Dombrowski JE, Hind SR, Martin RC, Stratmann JW (2011) Wound-ing systemically activates a mitogen-activated protein kinase in forage and turf grasses. Plant Sci 180:686–693. doi:10.1016/j.plantsci.2011.01.010

Farmer EE, Alméras E, Krishnamurthy V (2003) Jasmonates and related oxylipins in plant responses to pathogenesis and her-bivory. Curr Opin Plant Biol 6(4):372–378. doi:10.1016/S1369-5266(03)00045-1

Fester T, Hause G (2005) Accumulation of reactive oxygen spe-cies in arbuscular mycorrhizal roots. Mycorrhiza 15:373–379. doi:10.1007/s00572-005-0363-4

Fleiβner A, Glass NL (2007) SO, a protein involved in hyphal fusion in Neurospora crassa, localizes to septal plugs. Eukaryot cell 6(1):84–94. doi:10.1128/EC.00268-06

Curr Genet

1 3

Gailit J, Clark RA (1994) Wound repair in the context of extracellular matrix. Curr Opin Cell Biol 6(5):717–725. doi:10.1016/0955- 0674(94)90099-X

Gfeller A, Liechti R, Farmer EE (2010) Arabidopsis jasmonate signaling pathway. Sci Signal 3(109):cm4. doi:10.1126/scisignal.3109cm4

Gfeller A, Baerenfaller K, Loscos J, Chételat A, Baginsky S, Farmer EE (2011) Jasmonate controls polypeptide patterning in undam-aged tissue in wounded Arabidopsis leaves. Plant Physiol 156(4):1797–1807. doi:10.1104/pp.111.181008

Gurtner GC, Werner S, Barrandon Y, Longaker MT (2008) Wound repair and regeneration. Nature 453(7193):314–321. doi:10.1038/nature07039

Hagiwara D, Mizuno T, Abe K (2009) Characterization of NikA his-tidine kinase and two response regulators with special refer-ence to osmotic adaptation and asexual development in Asper-gillus nidulans. Biosci Biotechnol Biochem 73(7):1566–1571. doi:10.1271/bbb.90063

Hegedüs N, Sigl C, Zadra I, Pócsi I, Marx F (2011) The paf gene prod-uct modulates asexual development in Penicillium chrysogenum. J Basic Microbiol 51:253–262. doi:10.1002/jobm.201000321

Heil M (2009) Damaged-self recognition in plant herbivore defense. Trends Plant Sci 14:356–363. doi:10.1016/j.tplants.2009.04.002

Heil M (2012) Damaged-self recognition as a general strategy for injury detection. Plant Signal Behav 7(5):576–580. doi:10.4161/psb.19921

Heil M, Ibarra-Laclette E, Adame-Álvarez RM, Martínez O, Ram-irez-Chávez E, Molina- Torres J, Herrera-Estrella L (2012) How plants sense wounds: damaged-self recognition is based on plant-derived elicitors and induces octadecanoid signaling. PLoS One 7:e30357. doi:10.1371/journal.pone.0030537

Henis Y, Chet I, Avizohar-Hershenzon Z (1965) Nutritional and mechanical factors involved in mycelial growth and produc-tion of Sclerotial by Sclerotium rolfsii in artificial medium and amended soil. Phytopathol 55:87–91

Hernández-Oñate MA, Esquivel-Naranjo EU, Mendoza-Mendoza A, Stewart A, Herrera- Estrella AH (2012) An injury-response mechanism conserved across kingdoms determines entry of the fungus Trichoderma atroviride into development. Proc Natl Acad Sci USA 109:14918–14923. doi:10.1073/pnas.1209396109

Jaffe LF (2010) Fast calcium waves. Cell Calcium 48:102–113. doi:10.1016/j.ceca.2010.08.007

Jang HS, Han SJ, Kim JI, Lee S, Lipschutz JH, Park KM (2013) Activation of ERK accelerates repair of renal tubular epithe-lial cells, whereas it inhibits progression of fibrosis following ischemia/reperfusion injury. Biochim Biophys Acta Mol Basis Dis 1832:1998–2008. doi:10.1016/j.bbadis.2013.07.001

Jedd G (2011) Fungal evo-devo: organelles and multicellular complexity. Trends Cell Biol 21(1):12–19. doi:10.1016/j.tcb.2010.09.001

Jedd G, Chua N-H (2000) A new self-assembled peroxisomal vesi-cle required for efficient resealing of the plasma membrane. Nat Cell Biol 2:226–231. doi:10.1038/35008652

Jendretzki A, Winttland J, Wilk S, Straede A, Heinisch JJ (2011) How do I begin? Sensing extracellular stress to maintain yeast cell wall integrity. Eur J Cell Biol 90(9):740–744. doi:10.1016/j.ejcb.2011.04.006

Jiang F, Zhang Y, Dusting GJ (2011) NADPH oxidase-mediated redox signaling: roles in cellular stress response, stress tolerance, and tissue repair. Pharmacol Rev 63(1):218–242. doi:10.1124/pr.110.002980

Juvvadi PR, Maruyama JI, Kitamoto K (2007) Phosphorilation of the Aspergillus oryzae Woronin body protein, AoHex1, by protein kinase C: evidence for its role in the multimerization and proper localization of the Woronin body protein. Biochem J 405:533–540. doi:10.1042/BJ20061678

Kandoth PK, Ranf S, Pancholi SS, Jayanty S, Walla MD, Miller W, Howe GA, Lincoln DE, Stratmann JW (2007) Tomato MAPKs LeMPK1, LeMPK2, and LeMPK3 function in the systemin-medi-ated defense response against herbivorous insects. Proc Natl Acad Sci USA 104(29):12205–12210. doi:10.1073/pnas.0700344104

Kawate T, Michel JC, Birdsong WT, Gouaux E (2009) Crystal struc-ture of the ATP-gated P2X(4) ion channel in the closed state. Nature 460:592–598. doi:10.1038/nature08198

Kim M, McGinnis W (2011) Phosphorylation of grainy head by ERK is essential for wound-dependent regeneration but not for development of an epidermal barrier. Proc Natl Acad Sci USA 108:650–655. doi:10.1073/pnas.1016386108

Kim CY, Liu Y, Thorne ET, Yang H, Fukushige H, Gassmann W, Hildebrand D, Sharp RE, Zhang S (2003) Activation of a stress-responsive mitogen-activated protein kinase cascade induces the biosynthesis of ethylene in plants. Plant Cell 15:2707–2718. doi:10.1105/tpc.011411

Kobayashi M, Ohura I, Kawakita K, Yokota N, Fujiwara M, Shima-moto K, Doke N, Yoshioka H (2007) Calcium-dependent pro-tein kinases regulate the production of reactive oxygen spe-cies by potato NADPH oxidase. Plant Cell 19(3):1065–1080. doi:10.1105/tpc.106.048884

Koo AJK, Howe GA (2009) The wound hormone jasmonate. Phytochem 70(13–14):1571–1580. doi:10.1016/j.phytochem.2009.07.018

Koo AJ, Gao X, Daniel Jones A, Howe GA (2009) A rapid wound signal activates the systemic synthesis of bioac-tive jasmonates in Arabidopsis. Plant J 59(6):974–986. doi:10.1111/j.1365-313X.2009.03924.x

Kurashima Y, Amiya T, Nochi T, Fujisawa K, Haraguchi T, Iba H, Tsutsui H, Sato S, Nakajima S, Iijima H, Kubo M, Kunisawa J, Kiyono H (2012) Extracellular ATP mediates mast cell-depend-ent intestinal inflammation through P2X7 purinoceptors. Nat Commun 3:1034. doi:10.1038/ncomms2023

Kurusu T, Yagala T, Miyao A, Hirochika H, Kuchitsu K (2005) Identi-fication of a putative voltage-gated Ca2+ channel as a key regu-lator of elicitor-induced hypersensitive cell death mitogen-acti-vated protein kinase activation in rice. Plant J 42(6):798–809. doi:10.1111/j.1365-313X.2005.02415.x

Lamb C, Dixon RA (1997) The oxidative burst in plant disease resist-ance. Ann Rev Plant Physiol Plant Mol Biol 48(1):251–275. doi:10.1146/annurev.arplant.48.1.251

Land WG (2013) Transfusion-related acute lung injury: the work of DAMPs. Transfus Med Hemother 40(1):3–13. doi:10.1159/000345688

Land WG, Messmer K (2012) The danger theory in view of the injury hypothesis: 20 years later. Front Immunol 3:349. doi:10.3389/fimmu.2012.00349

Lara-Rojas F, Sánchez O, Kawasaki L, Aguirre J (2011) Asper-gillus nidulans transcription factor AtfA interacts with the MAPK SakA to regulate general stress responses, devel-opment spore functions. Mol Microbiol 80(2):436–454. doi:10.1111/j.1365-2958.2011.07581.x

Leiter É, Szappanos H, Oberparleiter C, Kaiserer L, Csernoch L, Pusztahelyi T, Emri T, Pócsi I, Salvenmoser W, Marx F (2005) Antifungal protein PAF severely affects the integrity of the plasma membrane of Aspergillus nidulans induces an apopto-sis-like phenotype. Antimicrob Agents Chemother 49(6):2445–2453. doi:10.1128/AAC.49.6.2445-2453.2005

Leitner M, Boland W, Mithöfer A (2005) Direct indirect defences induced by piercing-sucking chewing herbivores in Medicago truncatula. New Phytol 167:597–606. doi:10.1111/j.1469-8137.2005.01426.x

León J, Rojo E, Sánchez-Serrano JJ (2001) Wound signaling in plants. J Exp Bot 52(354):1–9. doi:10.1093/jexbot/52.354.1

Leonard TJ, Dick S (1968) Chemical induction of haploid fruiting bodies in Schizophyllum commune. Proc Natl Acad Sci USA 59:745–751 (PMCID: PMC224738)

Curr Genet

1 3

Leonard TJ, Dick S (1973) Induction of haploid fruiting by mechani-cal injury in Schizophyllum commune. Mycol 65:809–822. http://www.jstor.org/stable/3758520

Leonard TJ, Raper JR (1969) Schizophyllum commune: gene control-ling induced haploid fruiting. Science 165:190. doi:10.1126/science.165.3889.190

Li M, Guo W, Zhang P, Li H, Gu X, Yao D (2013) Signal flow path-ways in response to early Wallerian degeneration after rat sci-atic nerve injury. Neurosci Lett 536:56–63. doi:10.1016/j.neulet.2013.01.008

Liu F, Ng Kah, Seng LuY, Low W, Lai J, Jedd G (2008) Making two organelles from one: Woronin body biogenesis by peroxiso-mal protein sorting. J Cell Biol 180(2):325–339. doi:10.1083/jcb.200705049

Liu F, Lu Y, Pieuchot L, Dhavale T, Jedd G (2011) Import oligom-ers induce positive feedback to promote peroxisome differen-tiation control organelle abundance. Dev Cell 21(3):457–468. doi:10.1016/j.devcel.2011.08.004

Lulai EC, Corsini DL (1998) Differential deposition of suberin phenolic aliphatic domains their roles in resistance to infec-tion during potato tuber (Solanum tuberosumL.) wound-heal-ing. Physiol Mol Plant Pathol 53(4):209–222. doi:10.1006/pmpp.1998.0179

Maffei M, Bossi S, Spiteller D, Mithöfer A, Boland W (2004) Effects of feeding Spodoptera littoralis on lima bean leaves. I. Mem-brane potentials, intracellular calcium variations, oral secre-tions, regurgitate components. Plant Physiol 134(4):1752–1762. doi:10.1104/pp.103.034165

Markham P (1994) Occlusions of septal pores in filamen-tous fungi. Mycol Res 98(10):1089–1106. doi:10.1016/S0953-7562(09)80195-0

Martin P, Leibovich SJ (2005) Inflammatory cells during wound repair: the good, the bad the ugly. Trends Cell Biol 15(11):599–607. doi:10.1016/j.tcb.2005.09.002

Maruyama JI, Juvvadi PR, Ishi K, Kitamoto K (2005) Three-dimen-sional image analysis of plugging at the septal pore by Woronin body during hypotonic shock inducing hyphal tip bursting in the filamentous fungus Aspergillus oryzae. Biochem Biophys Res Commun 331:1081–1088. doi:10.1016/j.bbrc.2005.03.233

McCord JM (2000) The evolution of free radicals oxidative stress. Am J Med 108(8):652–659. doi:http://dx.doi.org/10.1016/S0002-9343(00)00412-5

Medders KE, Kaul M (2011) Mitogen-activated protein kinase p38 in HIV infection associated brain injury. J Neuroimmune Pharma-col 6(2):202–215. doi:10.1007/s11481-011-9260-0

Medina-Castellanos E, Esquivel-Naranjo EU, Heil M, Herrera-Estrella A (2014) Extracellular ATP activates MAPK and ROS signaling during injury response in the fungus Trichoderma atroviride. Front Plant Sci 5:659. doi:10.3389/fpls.2014.00659

Mendoza-Mendoza A, Pozo MJ, Grzegorski D, Martínez P, García JM, Olmedo-Monfil V, Cortés C, Kenerley C, Herrera-Estrella A (2003) Enhanced biocontrol activity of Trichoderma through inactivation of a mitogen-activated protein kinase. Proc Natl Acad Sci USA 100(26):15965–15970. doi:10.1073/pnas.2136716100

Miller G, Schlauch K, Tam R, Cortes D, Torres MA, Shualaev V, Dangl JL, Mittler R (2009) The plant NADPH oxidase RBOHD mediated rapid systemic signaling in response to diverse stim-uli. Sci Signal 2:ra45. doi:10.1126/scisignal.2000448

Mittler R, Vanderauwera S, Suzuki N, Miller G, Tognetti VB, Van-depoele K, Gollery M, Shulaev V, Breusegem FV (2011) ROS signaling: the new wave? Trends Plant Sci 16(6):300–309. doi:10.1016/j.tplants.2011.03.007

Momany M, Richardson EA, Van Sickle C, Jedd G (2002) Map-ping Woronin body position in Aspergillus nidulans. Mycol 94(2):260–266

Mosblech A, Feussner I, Heilmann I (2010) Oxylipin signaling plant growth. In: Munnik T (ed) Lipid signaling in plants, series: plant cell monographs, vol 16, pp 277–291. Springer, Berlin

Müller WH, Montijn RC, Humbel BM, van Aelst AC, Boon EJ, van der Krift TP, Boekhout T (1998) Structural differences between two types of basidiomycete septal pore caps. Microbiol 144:1721–1730. doi:10.1099/00221287-144-7-1721

Nam HJ, Jang IH, You H, Lee KA, Lee WJ (2012) Genetic evi-dence of a redox-dependent systemic wound response via Hayan protease-phenoloxidase system in Drosophila. EMBO J 31(5):1253–1265. doi:10.1038/emboj.2011.476

Nelson G, Kozlova-Zwinderman O, Collis AJ, Knight MR, Fincham JRS, Stanger CP, Hessing JGM, Punt PJ, van den Hondel CAMJ, Read ND (2004) Calcium measurement in living filamentous fungi expressing codon-optimized aequorin. Mol Microbiol 52(5):1437–1450. doi:10.1111/j.1365-2958.2004.04066.x

Noordermeer MA, Veldink GA, Vliegenthart JF (2001) Fatty acid hydroperoxide lyase: a plant cytochrome p450 enzyme involved in wound healing pest resistance. ChemBioChem 2(7–8): 494–504. doi:10.1002/1439-7633(20010803)2:7/8<494:AID-CBIC494>3.0.CO;2-1

Noverr MC, Erb-Downward JR, Huffnagle GB (2003) Produc-tion of eicosanoids other oxylipins by pathogenic eukaryotic microbes. Clin Microbiol Rev 16(3):517–533. doi:10.1128/CMR.16.3.517-533.2003

Orozco-Cardenas M, Ryan CA (1999) Hydrogen peroxide is gener-ated systemically in plant leaves by wounding systemin via the octadecanoid pathway. Proc Natl Acad Sci USA 96(11):6553–6557. doi:10.1073/pnas.96.11.6553

Orozco-Cárdenas ML, Narváez-Vásquez J, Ryan CA (2001) Hydrogen peroxide acts as a second messenger for the induc-tion of defense genes in tomato plants in response to wound-ing, systemin, methyl jasmonate. Plant Cell 13(1):179–191. doi:10.1105/tpc.13.1.179

Phillips L, Leonard TJ (1976) Extracellular intracellular phenoloxi-dase activity during growth development in Schizophyllum. Mycology 68:268–276. http://www.jstor.org/stable/3758998

Potters G, Pasternak TP, Guisez Y, Palme KJ, Jansen MAK (2007) Stress-induced morphogenic responses: growing out of trouble? Trends Plant Sci 12(3):98–105. doi:10.1016/j.tplants.2007.01.004

Rämet M, Lanot R, Zachary D, Manfruelli P (2002) JNK signaling pathway is required for efficient wound healing in Drosophila. Dev Biol 241:145–156. doi:10.1006/dbio.2001.0502

Reithner B, Schuhmacher R, Stoppacher N, Pucher M, Brunner K, Zeilinger S (2007) Signaling via the Trichoderma atroviride mitogen-activated protein kinase Tmk1 differentially affects mycoparasitism plant protection. Fungal Genet Biol 44:1123–1133. doi:10.1016/j.fgb.2007.04.001

Rodríguez-Peña JM, García R, Nombela C, Arroyo J (2010) The high-osmolarity glycerol (HOG) cell wall integrity (CWI) sig-nalling pathways interplay: a yeast dialogue between MAPK routes. Yeast 27(8):495–502. doi:10.1002/yea.1792

Romeis T, Piedras P, Zhang S, Klessig DF, Hirt H, Jones JD (1999) Rapid Avr9-Cf-9-dependent activation of MAP kinases in tobacco cell cultures leaves: convergence of resistance gene, elicitor, wound, salicylate responses. Plant Cell Online 11(2):273–287. doi:10.1105/tpc.11.2.273

Roncal T, Ugalde U (2003) Conidiation induction in Penicillium. Res Microbiol 154:539–546. doi:10.1016/S0923-2508(03)00168-2

Rusmin S, Leonard TJ (1978) Biochemical induction of fruiting in Schyzophyllum. Plant Physiol 61:538–543. doi:10.1104/pp.61.4.538

Sagi M, Davydov O, Orazova S, Yesbergenova Z, Ophir R, Stratmann JW, Fluhr R (2004) Plant respiratory burst oxidase homologs impinge on wound responsiveness development in Lycopersicon esculentum. Plant Cell 16(3):616–628. doi:10.1105/tpc.019398

Curr Genet

1 3

Sasaki H, Yamamoto H, Tominaga K, Masuda K, Kawai T, Teshima-Kondo S, Rokutan K (2009) NADPH oxidase-derived reactive oxygen species are essential for differentiation of a mouse mac-rophage cell line (RAW264.7) into osteoclasts. J Med Invest 56(1–2):33–41. doi:10.2152/jmi.56.33

Schilmiller AL, Howe GA (2005) Systemic signaling in the wound response. Curr Opin Plant Biol 8:369–377. doi:10.1016/j.pbi.2005.05.008

Seo S, Katou S, Seto H, Gomi K, Ohashi Y (2007) The mitogen-activated protein kinases WIPK SIPK regulate the levels of jasmonic salicylic acids in wounded tobacco plants. Plant J 49(5):899–909. doi:10.1111/j.1365-313X.2006.03003.x

Sherwood CL, Lantz RC, Burgess JL, Boitano S (2011) Arsenic alters ATP-dependent Ca2+ signaling in human airway epithelial cell wound response. Toxicol Sci 121:191–206. doi:10.1093/toxsci/kfr044

Steyaert JM, Weld RJ, Mendoza-Mendoza A, Stewart A (2010) Reproduction without sex: conidiation in the filamentous fun-gus Trichoderma. Microbiology 156:2887–9000. doi:10.1099/mic.0.041715-0

Steyaert JM, Weld RJ, Mendoza-Mendoza A, Krystofová S, Sim-kovic M, Varecka L, Stewart A (2013) Asexual development in Trichoderma: conidia to Chlamydospores. In: Mukherjee P, Horwitz BA, Singh US, Mukherjee M, Schmoll M (eds) Tricho-derma: biology and applications. CABI, Oxforshire, pp 87–109

Taj G, Agarwal P, Grant M, Kumar A (2010) MAPK machinery in plants: recognition response to different stresses through multiple signal transduction pathways. Plant Signal Behav 5(11):1370–1378. doi:10.4161/psb.5.11.13020

Takemoto D, Tanaka A, Scott B (2006) A p67phox-like regulator is recruited to control hyphal branching in a fugal-grass mutu-alistic symbiosis. Plant Cell 18:2807–2821. doi:10.1105/tpc.106.046169

Takemoto D, Tanaka A, Scott B (2007) NADPH oxidases in fungi: diverse roles of reactive oxygen species in fungal cellular dif-ferentiation. Fungal Genet Biol 44:1065–1076. doi:10.1016/j.fgb.2007.04.011

Takemoto D, Kamakura S, Saikia S, Becker Y, Wrenn R, Tanaka A, Sumimoto H, Scott B (2011) Polarity proteins Bem1 and Cdc24 are components of the filamentous fungal NADPH oxi-dase complex. Proc Natl Acad Sci USA 108(7):2861–2866. doi:10.1073/pnas.1017309108

Takeuchi O, Akira S (2010) Pattern recognition receptors inflamma-tion. Cell 140:805–820. doi:10.1016/j.cell.2010.01.022

Tenney K, Hunt I, Sweigard J, Pounder IJ, McClain C, Bowman JE, Bowman JB (2000) Hex-1, a gene unique to filamentous fungi, encodes the major protein of the Woronin body func-tions as a plug for septal pores. Fungal Genet Biol 31:205–217. doi:10.1006/fgbi.2000.1230

Tey WK, North AJ, Lu YF, Jedd G (2005) Polarized gene expression determines Woronin body formation at the leading edge of the fungal colony. Mol Biol Cell 16(6):2651–2659. doi:10.1091/mbc.E04-10-0937

Torres MA, Dangl JL, Jones JD (2002) Arabidopsis gp91phox hom-ologues AtrbohD AtrbohF are required for accumulation of

reactive oxygen intermediates in the plant defense response. Proc Natl Acad Sci USA 99(1):517–522. doi:10.1073/pnas.012452499

Torres J, Rivera A, Clark G, Roux SJ (2008) Participation of extracellular nucleotides in the wound response of Dasy-cladus vermicularis and Acetabularia acetabulum (Dasy-cladales and Chlorophyta). J Phycol 44:1504–1511. doi:10.1111/j.1529-8817.2008.00602.x

Tsitsigiannis DI, Keller NP (2007) Oxylipins as developmental host-fungal communication signals. Trends Microbiol 15(3):109–118. doi:10.1016/j.tim.2007.01.005

Watkins DN, Berman DM, Burkholder SG, Wang B, Beachy PA, Baylin SB (2003) Hedgehog signalling within airway epithe-lial progenitors in small-cell lung cancer. Nature 422:313–317. doi:10.1038/nature01493

White SR, Tse R, Marroquin BA (2005) Stress-activated protein kinases mediate cell migration in human airway epithelial cells. Am J Respir Cell Mol Biol 32:301–310. doi:10.1165/rcmb.2004-0118OC

Wu J, Baldwin IT (2010) New insights into plant responses to the attack from insect herbivores. Annu Rev Genet 44:1–24. doi:10.1146/annurev-genet-102209-163500

Wu J, Hettenhausen C, Meldau S, Baldwin IT (2007) Herbivory rap-idly activates MAPK signaling in attacked and unattacked leaf regions but not between leaves of Nicotiana attenuata. Plant Cell 19(3):1096–1122. doi:10.1105/tpc.106.049353

Yoo SK, Huttenlocher A (2009) Innate Immunity: wounds burst H2O2 signals to leukocytes. Curr Biol 19(14):553–555. doi:10.1016/j.cub.2009.06.025

Yuan P, Jedd G, Kumaran D, Swaminathan S, Shio H, Hewitt D, Chua AH, Swaminathan K (2003) A Hex-1 crystal lattice required for Woronin body function in Neurospora crassa. Nat Struct Biol 10(4):264–270. doi:10.1038/nsb910

Zeilinger S, Omann M (2007) Trichoderma biocontrol: signal trans-duction pathways involved in host sensing mycoparasitism. Gene Regul Syst Biol 1:227–234 (PMCID: PMC2759141)

Zeiser R, Penack O, Holler E, Idzko M (2011) Danger signals acti-vating innate immunity in graft-versus-host disease. J Mol Med 89:833–845. doi:10.1007/s00109-011-0767-x

Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, Brohi K, Itagaki K, Hauser CJ (2010) Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464(7285):104–107. doi:10.1038/nature08780

Zhao Z, Liu N, Huang J, Lu PH, Xu XM (2011) Inhibition of cPLA2 activation by Ginkgo biloba extract protects spi-nal cord neurons from glutamate excitotoxicity oxidative stress-induced cell death. J Neurochem 116:1057–1065. doi:10.1111/j.1471-4159.2010.07160.x

Zimmerman ZA, Kellogg DR (2001) The Sda1 protein is required for passage through start. Mol Biol Cell 12:201–219. doi:10.1091/mbc.12.1.201

Zorov DB, Bannikova SY, Belousov VV, Vyssokikh MY, Zorova LD, Isaev NK, Krasnikov BFY, Plotnikov E (2005) Reactive oxygen nitrogen species: friends or foes? Biochemistry (Mos) 70(2):215–221. doi:10.1007/s10541-005-0103-6