Figure 1. NLR mediated immune signaling.

Schematic presentation of CNL (Arabidopsis ZAR1 (1)), TNL (Arabidopsis RPP1 (2)) and helper NLR (Arabidopsis RNL NRG1.1 (3)) cell death and resistance signaling. (1) The bacterial effector AvrAc uridylates the receptor-like cytoplasmic kinase (RLCK) PBL2 resulting in PBL2^UMP. PBL2^UMP binds to the preformed ZAR1–RKS1 complex via interaction with RKS1, which induces a conformational change in the ZAR1–RKS1 complex resulting in nucleotide exchange (ADP to ATP) in the ZAR1 nucleotide-binding domain (NB-ARC) and eventually to the pentamerization of this tetrameric ZAR1–RKS1–PBL2^UMP complex into a so-called resistosome. The ZAR1 resistosome relocalizes to the plasma membrane and forms a calcium permeable cation channel via the N-terminal coiled-coil (CC) domains of the ZAR1 proteins [61,63]. (2) RPP1 recognizes and directly binds the oomycete-derived effector ATR1 via its leucine-rich repeat domain and the C-terminal jelly roll and Ig-like domain (C-JID). ATR1 binding induces the tetramerization of four RPP1-ATR1 sub-complexes into a RPP1 resistosome and thus a conformational activation or RPP1. Interactions between the RPP1 NB-ARC domains and the N-terminal TIR domains stabilize the resistosome complex without the necessity of ATP binding. RPP1 tetramerization results in the opening up of the NADase active site, transforming the TIR domains into an active holoenzyme [38]. Hydrolysis of NAD+ results in the production of various potential signaling molecules, such as variant cyclic ADPR (v-cADPR), that are hypothesized to activate and induce interaction of the TNL downstream signaling components EDS1, PAD4, SAG101 and the RNLs (helper NLRs). (3) How the EDS1/PAD4 or EDS1/SAG101 RNL components are activated by TIR domain NADase activity is not clear. Recently, it was shown that the Arabidopsis NRG1.1/NRG1A and ADR1 (both RNLs) can form activation-dependent oligomers and function also as calcium permeable cation channels at the plasma membrane [27,64]. Note: There is no experimental evidence yet that RNL resistosomes form ring-like structures (here a hexamere), which are similar to the pentameric ZAR1 ring-like resistosome. (4) It is known that NLR-activated effector-triggered immunity leads to calcium influx, which is required for cell death and resistance signaling, but how channel or pore formation by ZAR1 or NRG1.1/NRG1A is causing cell death (cell collapse) is not understood. It is possible that the calcium influx activates other cation channels important for immunity (for example the CNGCs) and components required for cell collapse, and that damage-associated molecular patterns (DAMPs) might also be released by the NLR formed pores to create signals enhancing immune responses that may lead to systemic resistance and maybe cell death. Created with BioRender.com.