NLR signaling in plants: from resistosomes to second messengers

Pathogen effector-induced assembly of resistosomes has been established as an important event for nucleotide binding and leucine-rich repeat-containing receptor (NLR) signaling in plants.The pentameric coiled-coil domain-containing NLR (CNL) resistosomes act as Ca2+-permeable channels, whereas the tetrameric Toll-interleukin 1-like receptor (TIR) NLR (TNL) resistosomes are NADase holoenzymes.TNL resistosomes catalyze the production of nucleotide-derived second messengers to activate the downstream helper NLRs activated disease resistance 1 (ADR1) and N requirement gene 1 (NRG1) of the CNL class. Thus, CNLs and TNLs converge on Ca2+ signals to trigger plant immunity.NLR signaling cross-talks with pattern-triggered immunity (PTI) signaling pathways.NLR signaling pathways in plants are negatively regulated by both hosts and pathogens. Nucleotide binding and leucine-rich repeat-containing receptors (NLRs) have a critical role in plant immunity through direct or indirect recognition of pathogen effectors. Recent studies have demonstrated that such recognition induces formation of large protein complexes called resistosomes to mediate NLR immune signaling. Some NLR resistosomes activate Ca2+ influx by acting as Ca2+-permeable channels, whereas others function as active NADases to catalyze the production of nucleotide-derived second messengers. In this review we summarize these studies on pathogen effector-induced assembly of NLR resistosomes and resistosome-mediated production of the second messengers of Ca2+ and nucleotide derivatives. We also discuss downstream events and regulation of resistosome signaling. Nucleotide binding and leucine-rich repeat-containing receptors (NLRs) have a critical role in plant immunity through direct or indirect recognition of pathogen effectors. Recent studies have demonstrated that such recognition induces formation of large protein complexes called resistosomes to mediate NLR immune signaling. Some NLR resistosomes activate Ca2+ influx by acting as Ca2+-permeable channels, whereas others function as active NADases to catalyze the production of nucleotide-derived second messengers. In this review we summarize these studies on pathogen effector-induced assembly of NLR resistosomes and resistosome-mediated production of the second messengers of Ca2+ and nucleotide derivatives. We also discuss downstream events and regulation of resistosome signaling. Plants rely on multiple receptors to detect invading microbial pathogens and mount immune responses 1.Ngou B.P.M. et al.Thirty years of resistance: zig-zag through the plant immune system.Plant Cell. 2022; 34: 1447-1478Crossref PubMed Scopus (45) Google Scholar,2.Zhou J.M. Zhang Y. Plant immunity: danger perception and signaling.Cell. 2020; 181: 978-989Abstract Full Text Full Text PDF PubMed Scopus (328) Google Scholar. One subfamily of plant immune receptors are pattern-recognition receptors (PRRs) (see Glossary) at the cell surface 1.Ngou B.P.M. et al.Thirty years of resistance: zig-zag through the plant immune system.Plant Cell. 2022; 34: 1447-1478Crossref PubMed Scopus (45) Google Scholar, 2.Zhou J.M. Zhang Y. Plant immunity: danger perception and signaling.Cell. 2020; 181: 978-989Abstract Full Text Full Text PDF PubMed Scopus (328) Google Scholar, 3.DeFalco T.A. Zipfel C. Molecular mechanisms of early plant pattern-triggered immune signaling.Mol. Cell. 2021; 81: 3449-3467Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar. PRRs recognize pathogen-associated molecular patterns (PAMPs) or host-derived damage-associated molecular patterns (DAMPs), leading to pattern-triggered immunity (PTI). PTI constitutes the first line of inducible plant defense against pathogens. Some pathogens can breach this layer of defense by secreting effector proteins into plant cells to dampen PTI. To counteract the virulence activity of the pathogen effectors, plants have evolved a second subfamily of immune receptors: intracellular NLRs. NLRs specifically recognize effector proteins, inducing effector-triggered immunity (ETI) and confer race-specific resistance to pathogens at the site of pathogen entry 1.Ngou B.P.M. et al.Thirty years of resistance: zig-zag through the plant immune system.Plant Cell. 2022; 34: 1447-1478Crossref PubMed Scopus (45) Google Scholar,2.Zhou J.M. Zhang Y. Plant immunity: danger perception and signaling.Cell. 2020; 181: 978-989Abstract Full Text Full Text PDF PubMed Scopus (328) Google Scholar,4.Jones J.D.G. et al.Intracellular innate immune surveillance devices in plants and animals.Science. 2016; 354aaf6395Crossref Google Scholar. PRRs and NLRs have different structures and subcellular localizations but mediate conserved downstream immune responses, including Ca2+ influx, bursts of reactive oxygen species (ROS), production of phytocytokines and defense phytohormones, and transcriptional reprogramming 1.Ngou B.P.M. et al.Thirty years of resistance: zig-zag through the plant immune system.Plant Cell. 2022; 34: 1447-1478Crossref PubMed Scopus (45) Google Scholar,2.Zhou J.M. Zhang Y. Plant immunity: danger perception and signaling.Cell. 2020; 181: 978-989Abstract Full Text Full Text PDF PubMed Scopus (328) Google Scholar. Probably for this reason, PTI and ETI are tightly connected 5.Yuan M. et al.Pattern-recognition receptors are required for NLR-mediated plant immunity.Nature. 2021; 592: 105-109Crossref PubMed Scopus (351) Google Scholar,6.Ngou B.P.M. et al.Mutual potentiation of plant immunity by cell-surface and intracellular receptors.Nature. 2021; 592: 110-115Crossref PubMed Scopus (329) Google Scholar. However, PTI and ETI differ in timing, amplitude, and duration of defense, which could be important in determining their different physiological outcomes. In addition to these responses, ETI also includes a hypersensitive response (HR), a form of rapid localized programmed cell death at the site of infection 7.Jones J.D. Dangl J.L. The plant immune system.Nature. 2006; 444: 323-329Crossref PubMed Scopus (8693) Google Scholar. NLRs are the largest intracellular immune receptors with hundreds of distinct members in different plant species 4.Jones J.D.G. et al.Intracellular innate immune surveillance devices in plants and animals.Science. 2016; 354aaf6395Crossref Google Scholar. NLRs have two conserved domains: a central nucleotide-binding and oligomerization domain (NOD), and a C-terminal leucine-rich repeat (LRR) domain. 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