Enzyme formation by immune receptors

doi:10.1126/science.abf2833

GSTDTAP > 气候变化

DOI	10.1126/science.abf2833
	Enzyme formation by immune receptors
	Lei Tian; Xin Li
	2020-12-04
发表期刊	Science
出版年	2020
英文摘要	Higher plants have evolved complex immune systems. Intracellular immune receptors known as nucleotide-binding leucine-rich repeat (NLR) proteins are present in both plants and animals; they are essential for immune responses ([ 1 ][1]). Upon infection, NLRs can recognize specific pathogen molecules and activate defense. In contrast to animals, which have a limited NLR repertoire, higher plants usually harbor hundreds of diverse NLR genes. However, little is known about their activation and signaling mechanisms. On pages 1184 and 1185 of this issue, Ma et al. ([ 2 ][2]) and Martin et al. ([ 3 ][3]), respectively, reveal the structure and activation mechanism of two NLRs: Arabidopsis thaliana RECOGNITION OF PERONOSPORA PARASITICA 1 (RPP1) and Nicotiana benthamiana RECOGNITION OF XOPQ 1 (ROQ1). Both NLRs self-assemble in a similar manner into tetrameric holoenzymes to activate defense responses upon direct effector recognition. There are two classes of typical plant NLRs for sensing pathogen effectors: Toll–interleukin-1 receptor (TIR)–type NLRs (TNLs) and coiled-coil (CC)–type NLRs (CNLs), which are defined by their different amino-terminal domains. As with mammalian NLRs, plant NLRs also contain a central nucleotide-binding domain (NBD) involved in oligomerization, as well as carboxyl-terminal leucine-rich repeats (LRRs) that often participate in auto-inhibition and ligand recognition ([ 1 ][1]). TNLs and CNLs are activated with dissimilar mechanisms and signal through different downstream components. Cryo–electron microscopy (cryo-EM) structural analysis of the A. thaliana CNL HOPZ-ACTIVATED RESISTANCE 1 (ZAR1) revealed that it assembles into a pentameric “resistosome” upon effector recognition, reminiscent of animal inflammasome rings that mediate innate immune responses ([ 4 ][4]). ZAR1 and an adaptor protein recognize the pathogen effector indirectly through monitoring the status of a host protein (called a decoy) that is directly targeted by the effector. The pentameric ring assembles upon binding of the effector-modified decoy, leading to the formation of a funnel-shaped structure composed of the amino-terminal CC domains of ZAR1. It has been hypothesized that this funnel associates with the cell membrane and triggers immune-related cell death ([ 5 ][5]). Until now, the resistosome structures of full-length TNLs have not been elucidated. TIR-containing proteins are widely present in bacteria, archaea, mammals, and higher plants ([ 6 ][6]). In mammals, TIR is a signature scaffold domain of immune receptors, including Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1Rs), and of some downstream adaptor proteins. Interactions of TIR domains between receptor and adaptor proteins are required for immune and inflammatory signal transduction. For example, TLR4 recruits the signaling adaptors MYD88 (myeloid differentiation primary response 88) and MAL (MYD88 adaptor-like) through TIR-TIR interactions, thereby activating downstream transcription factors such as nuclear factor κB (NF-κB) to induce inflammation ([ 7 ][7]). By contrast, a large number of TIR domains found in bacteria, archaea, and higher plants seem to serve as oxidized nicotinamide adenine dinucleotide (NAD+) hydrolases (NADases) upon self-association ([ 6 ][6], [ 8 ][8], [ 9 ][9]). TIR NADase activity was discovered in mammalian SARM1 (sterile alpha and TIR motif–containing protein 1), a major executor of neuronal axon degeneration ([ 10 ][10]). Like SARM1, TIR domains in a number of plant TNLs also exhibit NADase activity ([ 8 ][8], [ 9 ][9]). Cryo-EM analysis of full-length SARM1 revealed that in its resting state, it assembles into an octamer. The carboxyl-terminal Armadillo/HEAT motif (ARM) domains block the contact between adjacent TIRs through binding to NAD+ ([ 11 ][11]). With nicotinamide mononucleotide activator elicitation, the SARM1 octamer undergoes a conformational change, disrupting NAD+ binding sites of the ARM domains to enable TIR-TIR dimerization ([ 11 ][11], [ 12 ][12]). Interactions between the TIR domains then activate their NADase function. The depletion of NAD+ and the generation of products including nicotinamide, adenosine diphosphate ribose (ADPR), and cyclic ADPR (cADPR) together seem to serve as signals to trigger cell death. Because plant TNLs lack ARM domains, it was unclear whether plant TNLs form similar octamers or adopt a parallel self-inhibition mechanism. The A. thaliana TNL RPP1 recognizes its cognate effector protein ARABIDOPSIS THALIANA RECOGNIZED 1 (ATR1) from the oomycete pathogen Hyaloperonospora arabidopsidis . In nature, both RPP1 and ATR1 genes are highly polymorphic; different ATR1s are perceived by specific RPP1 variants ([ 13 ][13]). By contrast, the N. benthamiana TNL ROQ1 monitors Xanthomonas bacterial infections through direct recognition of the conserved effector XANTHOMONAS OUTER PROTEIN Q (XopQ) ([ 14 ][14]). RPP1 and ROQ1 both recognize their respective effectors ATR1 and XopQ through direct NLR-effector protein-protein interactions, which trigger strong immune responses to restrict pathogen colonization, including host cell death. ![Figure][15] Formation of a major type of plant resistosome Direct effector binding drives the tetramerization of a plant TNL receptor, such as RPP1 and ROQ1. Formation of the holoenzyme complex through their BB-loop enables NADase activity, activating downstream immune responses. GRAPHIC: A. KITTERMAN/ SCIENCE Ma et al. and Martin et al. used cryo-EM to determine the structures of the purified TNL-effector resistosome complexes. Despite the differences of the pairs, RPP1-ATR1 and ROQ1-XopQ form highly similar tetrameric clover-like structures (see the figure), which suggests that there may be a common activation mechanism for TNLs. These resistosome structures provide key insight about how RPP1 and ROQ1 can directly recognize their cognate effectors and tetramerize to promote NADase activity, thereby activating downstream immune responses. A structurally distinct domain was uncovered at the carboxyl termini of RPP1 and ROQ1, which is referred to as the C-terminal jelly-roll and Ig-like domain (C-JID). The C-JID and LRRs mediate effector binding specificity. Mutations of residues in these domains can disrupt their interaction interfaces with the effectors, resulting in reduced host cell death responses. For both RPP1 and ROQ1, direct binding of the effectors to the LRRs and C-JID likely releases the NBDs, which can then undergo conformational change and oligomerize into a tetramer. The tetrameric ring brings the TIR domains into close contact, allowing them to form the final active TNL resistosome with NADase holoenzyme activity. Intriguingly, unlike in ZAR1 and ROQ1 resistosomes, where deoxyadenosine triphosphate (dATP) and ATP are bound to the activated NLRs, RPP1 is bound by adenosine diphosphate (ADP) in the tetrameric ring, challenging the paradigm that NLRs are activated through exchanging ADP with ATP. Future analysis of additional TNL resistosomes may help to resolve the biological role of this observation. In both the RPP1 and ROQ1 resistosomes, tetramerization of the NBDs brings the four TIR domains close together. They form a two-fold dimer of dimers instead of a four-fold symmetric tetramer. The asymmetric TIR dimer forms one predicted NAD+ binding site while the symmetric TIR dimers stabilize the complex. Upon activation, two dimers arise in a head-to-tail manner mediated by the BB-loop (see the figure). Subsequent TIR NADase activity induces host cell death. Mutations of amino acids within the BB-loop that only affected the head-to-tail interactions were found to alter RPP1 and ROQ1 NADase activity and their function in immunity. Therefore, tetramerization of TIR domains of TNLs to form a holoenzyme likely represents a common activation mechanism for this large class of plant NLRs. Instead of homotetramerization as observed for ROQ1 and RPP1 resistosomes, hetero-NLR pairs with atypical domains or carboxyl-terminally truncated NLRs with only the TIR or TIR-NBD domains may serve to diversify the activation possibilities of these immune receptors in higher plants through heterotetramerization ([ 1 ][1]). The RPP1 and ROQ1 structures reveal a new type of TNL resistosome distinct from that of the CNL ZAR1. These findings represent a major step forward in understanding the activation mechanisms of plant TNLs. However, it remains unclear how the TIR NADase activity activates downstream immunity. In the two activated TNL resistosome structures reported by Ma et al. and Martin et al. , no NAD+ substrate was detected. One explanation could be that activated TIR domains quickly cleave NAD+. Alternatively, NAD+ may not be the preferred or only in planta substrate, because the detected in vitro NADase activities of plant TNLs are often weaker than those of bacterial TIRs and mammalian SARM1 ([ 8 ][8], [ 9 ][9]). Consequently, the complete spectrum of TNL TIR products should be investigated. Furthermore, the NADase activity of TNLs signals through key downstream components and helper NLRs (including the CNLs ADR1 and NRG1) for immune signaling in a manner that is still enigmatic ([ 15 ][16]). Finally, both RPP1 and ROQ1 resistosomes comprise TNLs that recognize their effectors directly. 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Supported by Natural Sciences and Engineering Research Council of Canada (NSERC)–Discovery and NSERC-CREATE-PRoTECT programs and by a scholarship from China Scholarship Council (L.T.). 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领域	气候变化 ; 资源环境
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/305821
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Lei Tian,Xin Li. Enzyme formation by immune receptors[J]. Science,2020.
APA	Lei Tian,&Xin Li.(2020).Enzyme formation by immune receptors.Science.
MLA	Lei Tian,et al."Enzyme formation by immune receptors".Science (2020).