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. 2015 Aug 27;169(2):1018–1026. doi: 10.1104/pp.15.00923

Cellular Signaling Pathways and Posttranslational Modifications Mediated by Nematode Effector Proteins1

Tarek Hewezi 1,*
PMCID: PMC4587465  PMID: 26315856

Plant-parasitic nematodes produce a diverse arsenal of effector proteins that interfere with defined cellular processes in host plants to promote successful parasitism.

Abstract

Plant-parasitic cyst and root-knot nematodes synthesize and secrete a suite of effector proteins into infected host cells and tissues. These effectors are the major virulence determinants mediating the transformation of normal root cells into specialized feeding structures. Compelling evidence indicates that these effectors directly hijack or manipulate refined host physiological processes to promote the successful parasitism of host plants. Here, we provide an update on recent progress in elucidating the molecular functions of nematode effectors. In particular, we emphasize how nematode effectors modify plant cell wall structure, mimic the activity of host proteins, alter auxin signaling, and subvert defense signaling and immune responses. In addition, we discuss the emerging evidence suggesting that nematode effectors target and recruit various components of host posttranslational machinery in order to perturb the host signaling networks required for immunity and to regulate their own activity and subcellular localization.

The root-knot (Meloidogyne spp.) and cyst (Globodera and Heterodera spp.) nematodes are sedentary endoparasites of the root system in a wide range of plant species. These obligate parasites engage in intricate relationships with their host plants that result in the transformation of normal root cells into specialized feeding sites, which provide the nematodes with all the nutrients required for their development. The initiation and maintenance of functional feeding cells by root-knot nematodes (giant cells) and cyst nematodes (syncytia) seems to be a dynamic process involving active dialogue between the nematodes and their host plants. The nematodes use their stylet, a needle-like apparatus, to deliver effector proteins into the host cells (Williamson and Hussey, 1996; Davis et al., 2004). These effector proteins are mainly synthesized in the nematode esophageal glands, which consist of one dorsal cell and two subventral cells. The activity of these glands is developmentally regulated, with secretions from the two subventral glands being most dynamic during the early stage of infection, consisting of root penetration, migration, and feeding site initiation. Secretions from the single dorsal cell seem to be more active during the sedentary stage of nematode feeding (Hussey and Mims, 1990).

Recent progress in the functional characterization of effector proteins from a number of phytonematodes has elucidated diverse mechanisms through which these effectors facilitate the nematode parasitism of host plants. One such mechanism involves depolymerization of the main structural polysaccharide constituents of the plant cell wall by using a diverse collection of extracellular effector proteins (Davis et al., 2011; Wieczorek, 2015). Another mechanism includes the molecular mimicry of host proteins in both form and function (Gheysen and Mitchum, 2011). This strategy could be highly successful when the nematode-secreted effectors imitate host functions to subvert cellular processes in favor of nematodes while escaping the regulation of host cellular processes. Another mechanism of effector action is the modulation of central components of auxin signaling to apparently generate unique patterns of auxin-responsive gene expression, leading to numerous physiological and developmental changes required for feeding site formation and development (Cabrera et al., 2015). In addition, cyst and root-knot nematodes have evolved to efficiently suppress defense responses during their prolonged period of sedentary biotrophic interaction with their hosts. Accordingly, a large number of nematode effectors are engaged in suppressing host immune responses and defense signaling (Hewezi and Baum, 2013; Goverse and Smant, 2014). Finally, there is accumulating evidence that nematode effector proteins target and exploit the host posttranslational machinery to the parasite’s advantage. Posttranslational modifications (PTMs) are tightly controlled and highly specific processes that enable rapid cellular responses to specific stimuli without the requirement of new protein synthesis (Kwon et al., 2006). Phosphorylation, ubiquitination, and histone modifications, among others, have recently been identified as fundamental cellular processes controlling immune signaling pathways (Stulemeijer and Joosten, 2008; Howden and Huitema, 2012; Marino et al., 2012; Salomon and Orth, 2013). This finding underscores the importance of targeting and coopting host posttranslational machinery by pathogen effectors to exert their virulence functions. Here, we review recent progress in the functional characterization of nematode effector proteins and the parasitic strategies that involve modifications of the plant cell wall, molecular mimicry of host factors, alteration of auxin signaling, subversion of defense signaling, and targeting and utilizing the host posttranslational machinery.

MODIFICATIONS OF THE PLANT CELL WALL

The plant cell wall is the main barrier facing endoparasitic nematodes during penetration and migration into root cells and tissues. While these parasites can use the stylet to rupture the plant cell wall, they also synthesize and secrete a diverse arsenal of extracellular effector proteins that function as cell wall-modifying enzymes. The structural complexity of the plant cell wall is reflected by the wide array of nematode-secreted enzymes that are able to depolymerize various structural polysaccharides of the cell wall, including cellulose, hemicellulose, and pectin (Davis et al., 2011; Bohlmann and Sobczak, 2014; Wieczorek, 2015). Given that the structural components of the plant cell wall vary significantly among plant species, it will be of interest to determine if these differences are reflected in the composition and diversity of cell wall-digesting enzymes in the genomes of nematodes parasitizing different plant species.

Sedentary parasitic nematodes also secrete other effector proteins, such as CELLULOSE-BINDING PROTEINs (CBPs), that function in plant cell wall modifications during the sedentary phase of parasitism. While CBPs from both cyst and root-knot nematodes do not contain any catalytic domain required for their activity, they were able to bind to cellulose in in vitro assays (Ding et al., 1998; Gao et al., 2004). Functional characterization of a CBP from the sugar beet (Beta vulgaris) cyst nematode Heterodera schachtii revealed that CBP functions through a direct association with Arabidopsis (Arabidopsis thaliana) PECTIN METHYLESTERASE PROTEIN3 (PME3; Hewezi et al., 2008). CBP overexpression increased PME3 activity in planta, thereby reducing the level of methylesterified pectin in cell walls and, hence, facilitating the access of other cell wall-modifying enzymes to cell wall polymers (Hewezi et al., 2008). Functional studies of other cell wall-digesting enzymes will provide further support to the critical roles of these effectors in nematode parasitism.

MIMICRY OF HOST FACTORS

Similar to other pathogens, plant-parasitic nematodes secrete effector proteins that mimic host proteins to apparently limit the capacity of the host immune system to respond to infection (Mitchum et al., 2012). One striking example of molecular mimicry employed by cyst nematodes is the secretion of effector proteins with a conserved C-terminal domain similar to that of plant CLAVATA3/ENDOSPERM SURROUNDING REGION-related (CLE) proteins (Mitchum et al., 2012). The CLE-like effectors seem to be unique to cyst nematodes, as no other CLE-like effectors have been identified outside cyst nematodes so far. The function of cyst nematode CLE-like effectors in mimicking endogenous plant peptides is supported by experimental data showing that overexpression of nematode CLE-like effectors in Arabidopsis produced a WUSCHEL phenotype (premature termination of shoot and floral meristems) similar to that of plant CLE overexpression (Wang et al., 2005, 2011; Lu et al., 2009). Nematode CLE-like effectors were also able to complement the Arabidopsis clavata3-2 (clv3-2) null mutant (Lu et al., 2009; Wang et al., 2010). Genetic and molecular analyses indicated that plant CLE peptides are perceived by various receptor-like kinases (RLKs) to mediate the downstream signaling essential for correct stem cell fate (Guo et al., 2010, 2011; Kinoshita et al., 2010). Similarly, it was shown recently that signaling pathways involving RLKs, specifically CLV1, the CLV2/CORYNE (CRN) heterodimer receptor complex, and RECEPTOR-LIKE PROTEIN KINASE2 (RLPK2), are required for nematode CLE signaling. Mutation of genes encoding CRN or RLPK2 resulted in significant decreases in both nematode infection and syncytium size (Replogle et al., 2011, 2013). These data suggest that nematode CLE-like effectors can associate with host RLKs to form a receptor-ligand complex and initiate signaling cascades, albeit aberrant, that are required for nematode parasitism. Identifying the molecular components of these signaling pathways will advance our understanding of the functional roles of CLE-like effectors in nematode parasitism and syncytium formation.

Another effector that may mimic the activity of host proteins is the 4F01 annexin-like effector from cyst nematodes. Annexins are calcium- and membrane-binding proteins with functions associated with a variety of biotic stresses (Lee et al., 2004). The H. schachtii annexin-like effector is structurally similar to annexins from both plants and animals (Patel et al., 2010). While 4F01 shares only 33% amino acid sequence identity with Arabidopsis annexin1 (annAt1), complementation of the annAt1 mutant by constitutive expression of Hs4F01 reversed mutant sensitivity to germination under high-salt stress, suggesting a functional similarity between nematode and plant annexins (Patel et al., 2010). Hs4F01 interacted specifically with an Arabidopsis oxidoreductase of the 2-oxoglutarate-Fe(II) oxygenase family, presumably to modulate plant stress response and defense signaling (Patel et al., 2010). More recently, an annexin-like effector was isolated from the cereal cyst nematode Heterodera avenae and was shown to suppress plant immunity to facilitate nematode parasitism (Chen et al., 2015a).

The secreted chorismate mutases (CMs) represent one of the most interesting groups of effectors found in a wide range of phytonematodes with different lifestyles and feeding behaviors. CM catalyzes the conversion of chorismate, the final product of the shikimate pathway, into prephenate. Chorismate is the precursor of the aromatic amino acids Phe, Tyr, and Trp and their derivatives, which include salicylic acid, indole-3-acetic acid, phytoalexins, flavonoids, and lignin (Knaggs, 2003). The complete absence of CM substrate in animals provided the first clue that parasitic nematodes use molecular mimicry of host proteins to modulate secondary metabolic pathways (Doyle and Lambert, 2003). While the exact function of the secreted CMs remains unknown, the wide distribution of this class of effector proteins in plant-parasitic nematodes (Jones et al., 2003, 2009; Huang et al., 2005; Lu et al., 2008; Vanholme et al., 2009; Haegeman et al., 2011; Yu et al., 2011) suggests that they have a fundamental and conserved function in parasitism across nematode species.

ALTERATION OF AUXIN SIGNALING

Consistent with the fundamental roles of phytohormones in cell differentiation and morphogenesis, several gene expression profiling experiments along with biochemical and genetic analyses have revealed the importance of various components of hormone signaling pathways, particularly those related to auxin, for the establishment of nematode feeding sites, (Grunewald et al., 2009; Goverse and Bird, 2011; Cabrera et al., 2015). Excitingly, the mechanisms through which these parasites regulate auxin transport and responses are now being uncovered. Two cyst nematode effector proteins were recently found to associate physically with key components of the auxin-signaling pathway. The 19C07 effector from H. schachtii was found to interact with the Arabidopsis auxin influx transporter LIKE AUXIN1 3 (LAX3) in the plasma membrane (Lee et al., 2011). Overexpression of 19C07 in Arabidopsis augmented the rate of lateral root emergence, an indication of increasing auxin influx. The functional analysis of the 19C07-LAX3 interaction suggests a regulatory module in which 19C07 likely functions to increase the activity of LAX3 in modulating auxin flow into root cells adjacent to the initial feeding cells, thereby facilitating their incorporation into the developing syncytium.

Another effector that directly targets host components of the auxin signaling pathway is the H. schachtii 10A07 effector. Arabidopsis INDOLE-3-ACETIC ACID INDUCIBLE16 (IAA16) was recently identified as a host target of 10A07 (Hewezi et al., 2015). IAA16 is a member of the AUXIN/IAA family that negatively regulates the expression of auxin response factors (ARFs; Chapman and Estelle, 2009). The expression pattern of IAA16 in the syncytium indicated a role in both the early stage of syncytium formation and during later stages of nematode infection. In addition, constitutive overexpression of IAA16 in Arabidopsis resulted in a significant increase in plant susceptibility to H. schachtii, whereas mutant alleles showed the opposite phenotype of reduced susceptibility. The proposed mode of function of 10A07-IAA16 interaction is that 10A07 impairs the ability of IAA16 to associate physically with ARFs, leading to the up-regulation of ARFs and the specific activation of auxin-dependent transcriptional programs. This mode of action was suggested from quantification of the expression of various ARFs that interact with IAA16 (Piya et al., 2014) in transgenic plants overexpressing 10A07 or IAA16. Interestingly, the expression of ARF6-8 and ARF6-19 was up-regulated in these transgenic plants during H. schachtii infection. Because these ARFs are highly up-regulated in the H. schachtii-induced syncytium (Hewezi et al., 2014) and have similar temporal and spatial expression patterns to IAA16, regulation of these ARFs by IAA16 in the syncytium is more than likely. Although these ARFs regulate different downstream targets, the 10A07/IAA16 association may trigger a specific subset of auxin-dependent transcriptional programs required for syncytium initiation and formation.

SUPPRESSION OF DEFENSE SIGNALING

Parasitic nematodes use a variety of effectors to directly or indirectly subvert host immune responses in order to mediate susceptibility. The secreted SPRY domain-containing (SPRYSEC) effector family identified in Globodera rostochiensis and Globodera pallida is the largest effector family found in plant parasitic nematodes to date (Rehman et al., 2009; Sacco et al., 2009; Postma et al., 2012; Cotton et al., 2014). Members of this family are involved in the modulation of plant immunity. The SPRYSEC Ran-binding protein from G. pallida (GpRBP1) induced programmed cell death in Nicotiana benthamiana leaves when coexpressed with the coiled-coil (CC) nucleotide-binding leucine-rich repeat (NB-LRR) resistance protein GPA2 from potato (Solanum tuberosum; Sacco et al., 2009). This finding suggests that GpRBP1 is recognized by GPA2 and triggers GPA2-mediated nematode resistance. Since GpRBP1 is present in both virulent and avirulent populations of G. pallida, its role in mediating nematode resistance is unclear and needs to be investigated in more detail. The effector SPRYSEC-19 of G. rostochiensis associated physically with the SW5-F CC-NB-LRR immune receptor (Postma et al., 2012). Surprisingly, this interaction did not elicit defense-related programmed cell death and resistance to G. rostochiensis but rather suppressed disease resistance mediated by several CC-NB-LRR immune receptors in agroinfiltration assays. These results suggest that SPRYSEC-19 may suppress the receptor-mediated immune response rather than initiate defense signaling (Postma et al., 2012). Recently, the expansin-like effector from G. rostochiensis (GrEXPB2) was found to suppress immunity-associated cell death induced by the Phytophthora infestans extracellular elicitor Necrosis and ethylene-inducing protein-Like Protein (PiNPP) and an autoactive mutant of the NB-LRR immune receptor Rx (Ali et al., 2015). These intriguing results demonstrate that immune responses initiated from both the apoplast (PiNPP) and cytoplasm (Rx) can be inhibited by GrEXPB2, proving the unprecedented example of an apoplastic effector that is able to inhibit NB-LRR responses. GrEXPB2 was also able to inhibit cell death induced by the NB-LRR Bs2 in combination with its cognate effector AvrBs2 (Bs2/AvrBs2) in the leaves of N. benthamiana and Nicotiana tabacum (Ali et al., 2015). Surprisingly, GrEXPB2 also elicited defense responses in a number of potato and tomato (Solanum lycopersicum) cultivars. The contradictory functions of GrEXPB2 in suppressing and inducing plant defenses are intriguing and deserve additional functional studies.

A number of cyst and root-knot nematode effectors has been shown to suppress host basal defenses to establish host compatibility. For instance, constitutive expression of the cyst nematode effector 10A06 in Arabidopsis resulted in increased susceptibility to H. schachtii as well as to other plant pathogens, including Pseudomonas syringae and the yellow strain of Cucumber mosaic virus (Hewezi et al., 2010). This suggests that 10A06 interferes with basal defense responses. The suppression of basal defense is likely due to the repression of salicylic acid signaling, because overexpression of 10A06 decreased expression of the salicylic acid-responsive pathogenesis-related genes PR-1, PR-2, and PR-5 (Hewezi et al., 2010). Interestingly, 10A06 interacts with Arabidopsis SPERMIDINE SYNTHASE2 (SPDS2), and experimental evidence indicates that modulating the endogenous level of reactive oxygen species is the key function of 10A06-SPDS2 interaction (Hewezi et al., 2010). Thus, cyst nematodes use the 10A06 effector to inhibit basal defenses by suppressing salicylic acid signaling and manipulating reactive oxygen species levels. The cyst nematode effector 30C02 also implicates nematode effectors in defense suppression. 30C02 directly targets β-1,3-endoglucanase, presumably to suppress its activity as a plant PR protein (Hamamouch et al., 2012). The reduced nematode susceptibility in Arabidopsis plants that overexpressed β-1,3-endoglucanase, and the opposite phenotype of increased susceptibility in the transfer DNA knockout line, indicate that this specific β-1,3-endoglucanase is an essential component of host defense response to be targeted by nematodes to promote infection. As another example, the Meloidogyne incognita calreticulin (MiCRT) effector was recently shown to play a role in the suppression of plant basal defenses during infection. Overexpression of MiCRT in Arabidopsis suppressed the induction of defense marker genes as well as callose deposition after treatment with the pathogen-associated molecular pattern elf18 (a synthetic peptide corresponding to the N-acetylated first 18 amino acids of elongation factor thermo unstable; Jaouannet et al., 2013). The mechanism of defense suppression by MiCRT remains elusive, but MiCRT, a calcium-binding protein, may chelate calcium in the apoplast and prevent calcium-dependent defense responses.

POSTTRANSLATIONAL MODIFICATIONS MEDIATED BY NEMATODE EFFECTORS

Phosphorylation

The 10A07 effector from H. schachtii that interacts physically with IAA16 (see above) also interacts with an Arabidopsis Ser/Thr protein kinase both in yeast and in planta (Hewezi et al., 2015). This host INTERACTING PROTEIN KINASE (IPK) phosphorylates 10A07 at Ser-144 and Ser-231. Ser-144 was found to be conserved in all known 10A07 family members, whereas Ser-231 was conserved in only two members, suggesting that Ser-231 may be the specificity determinant of 10A07 phosphorylation by IPK. A kinase-dead variant of IPK functioned antagonistically to the wild-type IPK and suppressed the 10A07-mediated nematode hypersusceptibility phenotype seen in the 10A07 overexpression lines. The finding that IPK promotes the trafficking of 10A07 from the cytoplasm to the nucleus revealed the importance of 10A07 phosphorylation to its function. This translocation is phosphorylation dependent, because mutations of the two phosphorylated Ser residues in the 10A07 protein impeded this trafficking, resulting in an exclusively cytoplasmic accumulation of 10A07. In contrast, the phosphomimic mutation of 10A07 was localized entirely in the nucleus. Phosphorylation-mediated 10A07 translocation to the nucleus is the key element of its mode of action. In the nucleus, 10A07 associates with the transcription factor IAA16 to alter auxin signaling in the nematode feeding site, as mentioned above (Fig. 1). However, it remains unknown how 10A07 coopts the host posttranslational machinery to execute such fundamental modifications to its virulence activity. One possibility is that this effector may structurally mimic a host substrate for host kinases to facilitate their phosphorylation.

Figure 1.

Figure 1.

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Nematode effector proteins involved in posttranslational modifications. Examples are shown of effectors involved in phosphorylation (10A07), ubiquitination (GrUBCEP12), glycosylation (GrCLE1), and proteolysis (VAP1). The H. schachtii 10A07 effector interacts physically with the plant IPK in the cytoplasm and is thereby phosphorylated. This phosphorylation mediates 10A07 translocation to the nucleus, where it binds to the IAA16 transcription factor to manipulate the expression of various ARFs. The G. rostochiensis UBCEP12 effector is processed in planta into a CEP12 peptide and free ubiquitin, apparently to suppress cell death associated with effector-triggered immunity (ETI) and to modulate the activity of the 26S proteasome, respectively. The G. rostochiensis VAP1 effector associates physically with the apoplastic papain-like Cys protease Rcr3pim, and this interaction perturbed the active site of Rcr3pim, leading to the activation of effector-triggered immunity mediated by the Cf-2 immune receptor. The G. rostochiensis multidomain CLE effector (GrCLE1) is glycosylated and processed into single-domain 12-amino acid arabinosylated glycopeptides, which are subsequently trafficked to the apoplast, where they bind to StCLV2 to activate CLE signaling pathways.

Another proficient way for pathogens to manipulate phosphorylation-mediated PTMs is by secreting effector proteins with functional kinase activity. Secreted kinases have been reported in animal pathogens and were found to interfere with various host cellular processes associated with pathogenesis (Shao, 2008; Sibley et al., 2009). In phytopathogens, however, this type of effector was only recently described in the secretome of P. infestans, the causal agent of late blight on potato and tomato (van Damme et al., 2012). The P. infestans CRN8 protein is the first reported secreted effector shown to have kinase activity associated with its virulence function (van Damme et al., 2012). Recent advances in identifying nematode effector repertoires revealed that plant-parasitic nematodes may also synthesize and secret effector proteins with significant similarity to protein kinases. For example, a novel effector candidate from the root-knot nematode M. incognita (Minc01696) was found to encode a putative TTK dual-specificity protein kinase with an intact kinase catalytic domain (Rutter et al., 2014). Another intriguing finding is that various protein kinases have been identified in the secretome of M. incognita (Bellafiore et al., 2008). Even though the actual translocation of these kinase-like effectors into host cells and tissues remains to be demonstrated, these putative effectors may function in various ways to alter host posttranslational machinery. These kinases may target and phosphorylate host proteins to induce aberrant signaling pathways required for infection. Because protein kinases generally form homodimers and heterodimers with other kinases to physically link the components of signal transduction pathways, these secreted kinases may form heterodimers with plant kinases, impacting their activity and subsequent downstream signaling. Taking into consideration the robustness of the topological conservation of kinase domains, these effectors may structurally mimic host kinases, hijacking plant defense signaling networks in order to cause disease.

Ubiquitination

Ubiquitination, the attachment of ubiquitin to a substrate protein, is a common PTM process in eukaryotic organisms. Ubiquitination involves the successive action of three enzymes: E1 (ubiquitin activating), E2 (ubiquitin conjugating), and E3 (ubiquitin ligase; Vierstra, 2009). Tagging substrate proteins with ubiquitin can alter their subcellular localization, activity, association with other proteins, or signal for their degradation via the 26S proteasome (Trujillo and Shirasu, 2010; Marino et al., 2012; Callis, 2014). Ubiquitin proteins are highly conserved in eukaryotes and can be divided into two main classes: polyubiquitin proteins and ubiquitin carboxyl extension proteins (UBCEPs; Vierstra, 2009). The polyubiquitin proteins contain repeats of the ubiquitin domain (76 amino acids) in a contiguous manner. In contrast, the UBCEP proteins contain a single ubiquitin domain with a carboxyl extension protein (CEP) domain that is proteolytically cleaved following translation.

A UBCEP effector was first identified from Heterodera glycines (Gao et al., 2003), and homologous sequences were later identified from other cyst and root-knot nematode species (Tytgat et al., 2004; Bellafiore et al., 2008; Jones et al., 2009; Chronis et al., 2013), suggesting a conserved function in pathogenesis across parasitic nematodes. Recently, a UBCEP effector from the potato cyst nematode G. rostochiensis (GrUBCEP12) was shown to play a vital role in the parasitism of potato plants. Overexpression of GrUBCEP12 in potato resulted in increased plant susceptibility to G. rostochiensis, whereas knocking down UBCEP12 expression in the nematode via host-derived RNA interference led to the opposite phenotype of reduced susceptibility (Chronis et al., 2013). Interestingly, GrUBCEP12 was processed into free ubiquitin and a CEP12 peptide in planta. This cleavage was further confirmed when mutation in the ubiquitin cleavage site rendered the protein intact (Chronis et al., 2013). Interestingly, the cleaved CEP12 peptide suppressed resistance gene-mediated cell death. Furthermore, a target search analysis pointed to a role of the free ubiquitin in suppressing plant defense by affecting the host 26S proteasome. Taken together, these results suggest that the UBCEP12 effector protein is processed in the same way as the canonical UBCEPs, producing free ubiquitin and a short CEP12 peptide; hence, UBCEP12 can perform dual functions (Fig. 1). The 12-amino acid CEP12 peptide functions in suppressing cell death associated with effector-triggered immunity, whereas the free ubiquitin eventually impacts host protein stability via the 26S proteasome (Fig. 1).

Glycosylation

Glycosylation is the covalent addition of carbohydrate molecules to a protein. It is considered the most complex PTM process, as it largely impacts the biophysical characteristics of proteins (Shental-Bechor and Levy, 2009; Gomord et al., 2010). The ability of cyst nematode CLE-like effectors to complement the Arabidopsis clv3-2 null mutant provided the first clue that these effectors should undergo PTMs and proteolytic processing, similar to that of plant CLE precursors, to become bioactive CLE peptides (Shinohara and Matsubayashi, 2010; Shinohara et al., 2012; Okamoto et al., 2013). Consistent with this hypothesis, a recent study demonstrated that a multidomain CLE effector from G. rostochiensis (GrCLE1) was glycosylated and processed into 12-amino acid arabinosylated glycopeptides (GrCLE1-1Hyp4,7g), similar in structure to bioactive plant CLE peptides (Chen et al., 2015b). It was further demonstrated that this glycosylated peptide is more resistant to hydrolytic degradation and binds with much higher affinity to the potato CLV2-like receptor (StCLV2) than its nonglycosylated forms (Fig. 1). These data provide direct evidence that cyst nematodes have evolved to recruit host posttranslational and processing machinery to convert CLE-like effectors into biologically active peptides.

Proteolysis

Another PTM employed by nematode effectors is proteolysis of targeted host proteins. Effectors with strong similarity to proteases have been identified from both cyst and root-knot nematodes. The aspartyl protease-like effector from M. incognita (MiASP2) was secreted into the apoplasm during the intercellular migration of infective juveniles as well as during the early sedentary stages of giant cell formation (Vieira et al., 2011). While the proteolytic activity of MiASP2 has not been demonstrated, it may contribute to host range determination through the degradation of specific host proteins, a mode of action similar to the aspartic proteases from the animal-parasitic helminths (Brinkworth et al., 2000; Williamson et al., 2003). Consistent with this idea, protease-like effectors have been identified in M. incognita (Neveu et al., 2003; Danchin et al., 2013), G. pallida (Jones et al., 2009), H. glycines (Noon et al., 2015), and Meloidogyne chitwoodi (Roze et al., 2008). Phytonematodes not only secrete protease-like effectors but also target host proteases. The venom allergen-like protein from G. rostochiensis (GrVAP1) interacted with the apoplastic papain-like Cys protease Rcr3pim from the red currant tomato (Solanum pimpinellifolium), and this interaction perturbed the active site of Rcr3pim (Lozano-Torres et al., 2012). Plants have evolved guard proteins that can sense and detect effector-mediated PTMs of host proteins to activate immune responses (van der Hoorn and Kamoun, 2008). In this context, Rcr3pim was found to be guarded by the resistance protein Cf-2 that then triggered a defense-related programmed cell death upon sensing perturbations in Rcr3pim mediated by GrVAP1 (Lozano-Torres et al., 2012; Fig. 1). In the absence of the Cf-2 immune receptor, Rcr3pim was shown to enhance plant susceptibility to infection by G. rostochiensis, highlighting the role of Rcr3pim as a virulence target of this nematode. Cf-2 was originally identified as an immune receptor conferring resistance to the fungal pathogen Cladosporium fulvum, and this resistance requires the binding of the fungal effector Avr2 to Rcr3pim (Krüger et al., 2002; Rooney et al., 2005). Thus, Cf-2’s guarding of Rcr3pim is a fascinating example of how an immune receptor detects PTMs induced by two structurally unrelated effectors from two different types of plant pathogens.

Histone Modifications

One common PTM includes histone modifications. Histone proteins are subjected to a variety of biochemical modifications, such as acetylation and methylation, which frequently occur at Lys residues. Modifications in these proteins result in significant changes in chromosome structure and gene expression (Suganuma and Workman, 2011). Despite accumulating evidence that the modulation of host histones and chromatin by plant pathogens is a widespread mechanism for inducing susceptibility (Alvarez et al., 2010), there is scant evidence that pathogen effectors directly mediate chromatin modification. In this context, a nematode effector protein that may induce modifications of histones has been identified from G. pallida with strong sequence similarity to Physcomitrella patens SIN3 histone deacetylase (Jones et al., 2009). However, its role in histone modification, if any, remains to be clarified.

CONCLUSION AND FUTURE DIRECTIONS

With the rapid progress in sequencing technologies, whole-genome sequencing has become a practical option, and in the near future, we expect complete genome sequences of several nematode species to be available. This will facilitate the identification of the complete effector repertoires from various phytonematodes and even from different populations of the same species. Comparative analysis of these effector suites will facilitate elucidation of the mechanisms that govern nematode pathogenicity and host ranges. Such analysis may also point to specific sets of effectors associated with particular modes of parasitism.

The discovery of an ever-increasing number of effector proteins from various nematode species has significantly expanded our knowledge of the complexity of nematode effector repertoires. Given the fact that only a small portion of these effectors has been functionally characterized, the challenge that lies ahead is to determine the mode of action of these effectors and elucidate the molecular mechanisms underlying nematode parasitism of host plants. Identifying host targets using large-scale interactome studies followed by integrated functional assays will be necessary to build a mechanistic understanding of effector functions in plant cells.

The recent findings we have discussed together demonstrate that PTMs mediated by nematode effectors profoundly influence the interfaces between host plants and parasitic nematodes through a variety of mechanisms. Many unique and important protein functions depend on appropriate PTMs, and these modifications cannot be directly identified at the transcriptional or translational level. Instead, this requires comprehensive proteomic analyses of PTMs of host proteins to uncover critical and as-yet-unknown mechanisms that are responsible for infection-associated signaling and cellular processes. Taking into consideration the recent advances of proteome-wide identification of posttranslationally modified proteins (Chuh and Pratt, 2015), it will be possible in the near future to draw a comprehensive picture of the varied and coordinated PTMs that are associated with nematode pathogenicity. Because the sophisticated and complex molecular mechanisms controlling host immune responses involve an elevated level of proteomic plasticity to which PTMs contribute decisively, understanding PTMs mediated by nematode effectors will eventually lead to the development of innovative and improved nematode resistance strategies.

Compelling evidence indicates that cyst nematodes target and manipulate the expression of several main components of epigenetic machinery, including small interfering RNAs, microRNAs, and DNA methylation (Hewezi et al., 2008, 2012; Li et al., 2012; Rambani et al., 2015). This raises the question of how nematodes use their effectors to modify the epigenome of infected host cells. Genome-wide approaches for DNA methylation and histone modifications combined with next-generation transcriptomics approaches, such as RNA sequencing and small RNA sequencing, will prove valuable for unveiling the epigenetic mechanisms that phytonematodes employ to manipulate their hosts in order to cause disease. This will provide opportunities for researchers to develop epigenetic signatures that may correlate with plant susceptibility or resistance. Developing epigenetic signatures, whether in part or entirely genetically controlled, that can mark nematode infection and disease progression will provide a novel strategy for identifying nematode-resistant germplasm in breeding programs.

Acknowledgments

I thank Dr. Tessa Burch-Smith for comments and suggestions.

Glossary

PTM

posttranslational modification

RLK

receptor-like kinase

CM

chorismate mutase

CC

coiled-coil

NB-LRR

nucleotide-binding leucine-rich repeat

Footnotes

1

This work was supported by the National Science Foundation (grant no. 1145053), the Tennessee Soybean Promotion Board, and the University of Tennessee, Institute of Agriculture.

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