The activation of plant NLRs occur either as a result of direct recognition of pathogen-secreted effectors, or by detecting effector-mediated manipulation of host components involved in immune signalling or mimic thereof (including ‘sensor’ or ‘decoy’ domains integrated within NLRs)2,7,9-12. Consequently, genetically induced loss or alteration of these ‘guardees’ can inadvertently cause NLR activation and autoimmunity. As such, genes whose mutation caused these autoimmune phenotypes could be classified a negative regulators of immunity, e.g. MPK4107. However, with the identification of NLR mutants (eg. summ2110) that suppress these autoimmune phenotypes, it is now postulated that many important immune components are actually ‘guarded’, leading to misinterpretation of results solely based on loss-of-function genetic eveidence60. Accordingly, while clearly involved in PTI as positive regulators, loss of BAK1, BIK1 and RBOHD, for example, in addition to MPK4, leads to autoimmune phenotypes. Interestingly, many effectors secreted by plant pathogenic bacteria redundantly target PTI components including BAK1, BIK1 and MAPKs196. Thus, the identification of the NLRs that guard these important immune components is of great interest, not only for academic reasons, but also as they may enable us to engineer disease resistance against the important pathogens that secrete these effectors.
BOX 2: Manipulation of plant pattern-triggered immunity by bacterial effectors
A common feature of Gram-negative pathogenic bacteria is the use of the type III secretion system (T3SS) to inject effector proteins (virulence factors) directly into host cells. These effectors manipulate host cells to the pathogen advantage, and can suppress plant immunity by targeting key signalling components196.
Similar to host phosphatases that negatively regulate PRR complexes, bacterial effectors interfere with the phosphorylation status of PRR complexes to block the early steps of PTI signalling. The P. syringae effector AvrPto acts as general kinase inhibitor, targeting receptor kinases, such as FLS2 and EFR, to inhibit PTI responses triggered by multiple PAMPs197,198. Another P. syringae effector, HopAO1, displays tyrosine phosphatase activity and inhibits elf18-triggered immunity by dephosphorylating EFR tyrosine residues199. The Xanthomonas campestris effector AvrAC possesses a previously uncharacterized uridylyl transferase activity that modifies key phosphorylation sites of several RLCKs, including BIK1, to block their kinase activities and thus PTI signalling113. Remarkably, Arabidopsis detects AvrAC virulence by using the decoy substrate PBL2, which is guarded by the NLR ZAR1200. Additionally, the X. oryzae effector Xoo1418, of unknown enzymatic function, interacts with several rice RLCKs and prevents CERK1-dependent phosphorylation of OsRLCK185, suppressing both PGN- and chitin-triggered immune responses80.
HopAI1 from P. syringae permanently inactivates MAPKs by removing the phosphate group of phospho-threonines201; however, its action on Arabidopsis MPK4 is recognized by the NLR SUMM2110. In addition, HopF2, also from P. syringae, ADP-ribosylates and inactivates MKK5 to prevent downstream activation of MPKs202.
Some bacterial effectors target immune signalling components for degradation: the P. syringae cysteine protease AvrPphB cleaves BIK1 and other PBLs76, which effect can be recognized by the NLR RPS5203,204; whereas AvrPtoB functions as an ubiquitin E3 ligase to promote degradation of FLS2, EFR and CERK172,205,206. Additionally, AvrPtoB can also act as a kinase inhibitor to inactivate BAK1 and the tomato orthologue of AtCERK1, SlBti9207,208.
Several bacterial effectors subvert jasmonic acid signalling in their favour. RIN4 is an intrinsically disordered protein conserved across plants and was recently found to play an important role in jasmonic acid signalling and stomatal opening by regulating the H+-ATPase AHA1209,210. Interestingly, a number of effectors have been found to target RIN4, but Arabidopsis RIN4 is guarded by two NLRs, RPS2 and RPM1211-213. In addition, the P. syringae effectors HopZ1a and HopX1 promote degradation of JAZ proteins, the key repressors of jasmonic acid signalling214,215.
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Acknowledgments
The authors would like to thank all members of the Zipfel laboratory for fruitful discussions, especially Nicholas Holton and Martin Stegmann, as well as Sara Ben Khaled, for critically reading the manuscript before submission. DC was supported by a PhD scholarship (reference SFRH/BD/79088/2011) from Fundação para a Ciência e a Tecnologia (FCT). Research in the Zipfel laboratory is funded by the Gatsby Charitable Foundation, the European Research Council (ERC), the UK Biotechnology and Biological Sciences Research Council (BBSRC), and the Two Blades Foundation.
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