Although several cognate R-Avr pairs have been identified, the relationship between these pairs is not always well understood at the molecular level. The simplest model predicts that R proteins are receptors for Avr ligands. For example, it has been shown that the R protein Pto interacts directly with its cognate effector AvrPto, and that this interaction is necessary for resistance (Tang et al. 1996) . Although there are a few other cases, most attempts to show direct interactions between R and Avr proteins have not been fruitful, suggesting that additional host proteins are involved in effector recognition. In 1998, Eric Van der Biezen and Jonathan Jones introduced the idea that, as opposed to directly interacting with effector proteins, R proteins might guard or monitor the integrity of effector targets (Van der Biezen and Jones 1998); an idea that was later articulated as the "guard hypothesis" (Dangl and Jones 2001). In this model, R proteins screen for pathogen-induced modifications in host proteins to trigger immune signaling.
A well-established example of such a pathogen-modified protein in plants is RIN4 (RPM1-INTERACTING PROTEIN4). RIN4 is localized to the plasma membrane, and is monitored by the likewise localized CC-NB-LRR R proteins RPM1 (RESISTANCE
TO P syringae pv. maculicolal) and RPS2 (RESISTANT TO P syringae2). During infection, P syringae releases several effectors into plant cells, including AvrRpml, AvrB, and AvrRpt2, which are thought to target a number of host proteins as part of a virulence strategy. AvrRpt2, for example, is a cysteine protease (Coaker et al. 2005) that modifies plant auxin levels to promote virulence and pathogen growth (Chen et al . 2007). Although most virulence targets of these effectors have not been identified, it has been shown that AvrRpml, AvrB, and AvrRpt2 interact with and modify RIN4 either by phosphorylation or cleavage (Mackey et al. 2002; Axtell et al. 2003). Intriguingly, these interactions with RIN4 do not promote virulence and are not required for successful infection (Belkhadir et al. 2004). Instead, RIN4 phosphorylation is monitored by RPM1 and its cleavage is monitored by RPS2, and either event leads to plant resistance (Mackey et al. 2002; Kim et al. 2005). RIN4 physically interacts with and represses both RPM1 and RPS2 (Mackey et al. 2002, 2003). The inhibitory function of RIN4 has been shown genetically, as partial loss-of-function rin4 mutant plants have heightened resistance to virulent pathogens, suggesting a negative role in immunity (Mackey et al. 2002) . Also, rin4 phenotypes are fully suppressed in rin4 rpml rps2 triple mutants, indicating that RIN4 is indeed a negative regulator of these R proteins (Belkhadir et al. 2004). Another example is AvrPto, which, as mentioned before, targets the PRRs FLS2 and EFR to suppress plant immunity. AvrPto also binds and inhibits the kinase Pto (Xing et al. 2007) . but unlike binding FLS2 and EFR, this interaction activates the NB-LRR protein Prf (Pseudomonas resistance and fenthion sensitivity) and leads to resistance (Mucyn et al. 2006). Thus, Pto might have evolved to compete with FLS2 and ERF binding to initiate defense (Zipfel and Rathjen 2008). The guard hypothesis predicts that R proteins evolved to keep a watchful eye on a subset of proteins that are modified by pathogen effectors (including some plant proteins that may mimic virulence targets; Xing et al. 2007). It is likely that most effector modifications augment virulence in some way; however, the detection of even one of these events in a plant expressing the appropriate R protein can lead to an immune response and render the pathogen avirulent (Belkhadir et al. 2004).
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