scholarly journals Structural and biochemical mechanisms of NLRP1 inhibition by DPP9

Nature ◽  
2021 ◽  
Author(s):  
Menghang Huang ◽  
Xiaoxiao Zhang ◽  
Gee Ann Toh ◽  
Qin Gong ◽  
Jia Wang ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Complex Formation ◽  
Enzymatic Activity ◽  
Resting Cells ◽  
Leucine Rich Repeat ◽  
Nucleotide Binding Domain ◽  
Functional Assays ◽  
Biochemical Mechanisms ◽  
Dipeptidyl Peptidases ◽  
Shed Light

AbstractNucleotide-binding domain, leucine-rich repeat receptors (NLRs) mediate innate immunity by forming inflammasomes. Activation of the NLR protein NLRP1 requires autocleavage within its function-to-find domain (FIIND)1–7. In resting cells, the dipeptidyl peptidases DPP8 and DPP9 interact with the FIIND of NLRP1 and suppress spontaneous NLRP1 activation8,9; however, the mechanisms through which this occurs remain unknown. Here we present structural and biochemical evidence that full-length rat NLRP1 (rNLRP1) and rat DPP9 (rDPP9) form a 2:1 complex that contains an autoinhibited rNLRP1 molecule and an active UPA–CARD fragment of rNLRP1. The ZU5 domain is required not only for autoinhibition of rNLRP1 but also for assembly of the 2:1 complex. Formation of the complex prevents UPA-mediated higher-order oligomerization of UPA–CARD fragments and strengthens ZU5-mediated NLRP1 autoinhibition. Structure-guided biochemical and functional assays show that both NLRP1 binding and enzymatic activity are required for DPP9 to suppress NLRP1 in human cells. Together, our data reveal the mechanism of DPP9-mediated inhibition of NLRP1 and shed light on the activation of the NLRP1 inflammasome.

scholarly journals Structural and biochemical mechanisms of NLRP1 inhibition by DPP9

2020 ◽  
Author(s):  
Menghang Huang ◽  
Xiaoxiao Zhang ◽  
Toh Gee Ann ◽  
Qin Gong ◽  
Jia Wang ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Enzymatic Activity ◽  
Resting Cells ◽  
Leucine Rich Repeat ◽  
State Structure ◽  
Nucleotide Binding Domain ◽  
Functional Assays ◽  
Related Enzyme ◽  
Biochemical Mechanisms ◽  
Shed Light

AbstractThe nucleotide-binding domain (NBD) and leucine-rich repeat (LRR)-containing receptors (NLRs) mediate innate immunity by forming inflammasomes. Activation of the NLR protein NLRP1 requires auto-cleavage within its FIIND domain1–7. In resting cells, the dipeptidyl peptidase DPP9 interacts with NLRP1-FIIND and together with a related enzyme DPP8, suppresses spontaneous NLRP1 activation8,9. The mechanisms of DPP8/9-mediated NLRP1 inhibition, however, remain elusive. Here we provide structural and biochemical evidence demonstrating that rat NLRP1 (rNLRP1) interacts with rDPP9 in a stepwise manner to form a 2:1 complex. An auto-inhibited rNLRP1 molecule first interacts with rDPP9 via its ZU5 domain. This 1:1 rNLRP1-rDPP9 complex then captures the UPA domain of a second rNLRP1 molecule via a UPA-interacting site on DPP9 and dimeric UPA-UPA interactions with the first rNLRP1. The 2:1 rNLRP1-rDPP9 complex prevents NLRP1 UPA-mediated higher order oligomerization and maintains NLRP1 in the auto-inhibited state. Structure-guided biochemical and functional assays show that both NLRP1-binding and its enzymatic activity are required for DPP9 to suppress NLRP1, supporting guard-type activation of the NLR. Together, our data reveal the mechanism of DPP9-mediated inhibition of NLRP1 and shed light on activation of the NLRP1 inflammasome.

scholarly journals Structural and biochemical mechanisms of NLRP1 inhibition by DPP9

2020 ◽  
Author(s):  
Jijie Chai ◽  
Menghang Huang ◽  
Xiaoxiao Zhang ◽  
Toh Gee Ann ◽  
Qin Gong ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Enzymatic Activity ◽  
Resting Cells ◽  
Leucine Rich Repeat ◽  
State Structure ◽  
Nucleotide Binding Domain ◽  
Functional Assays ◽  
Related Enzyme ◽  
Biochemical Mechanisms ◽  
Shed Light

Abstract The nucleotide-binding domain (NBD) and leucine-rich repeat (LRR)-containing receptors (NLRs) mediate innate immunity by forming inflammasomes. Activation of the NLR protein NLRP1 requires auto-cleavage within its FIIND domain1-7. In resting cells, the dipeptidyl peptidase DPP9 interacts with NLRP1-FIIND and together with a related enzyme DPP8, suppresses spontaneous NLRP1 activation8,9. The mechanisms of DPP8/9-mediated NLRP1 inhibition, however, remain elusive. Here we provide structural and biochemical evidence demonstrating that rat NLRP1 (rNLRP1) interacts with rDPP9 in a stepwise manner to form a 2:1 complex. An auto-inhibited rNLRP1 molecule first interacts with rDPP9 via its ZU5 domain. This 1:1 rNLRP1-rDPP9 complex then captures the UPA domain of a second rNLRP1 molecule via a UPA-interacting site on DPP9 and dimeric UPA-UPA interactions with the first rNLRP1. The 2:1 rNLRP1-rDPP9 complex prevents NLRP1 UPA-mediated higher order oligomerization and maintains NLRP1 in the auto-inhibited state. Structure-guided biochemical and functional assays show that both NLRP1-binding and its enzymatic activity are required for DPP9 to suppress NLRP1, supporting guard-type activation of the NLR. Together, our data reveal the mechanism of DPP9-mediated inhibition of NLRP1 and shed light on activation of the NLRP1 inflammasome.

scholarly journals NLR signaling network mediates immunity to diverse plant pathogens

2016 ◽  
Author(s):  
Chih-Hang Wu ◽  
Ahmed Abd-El-Haliem ◽  
Tolga O. Bozkurt ◽  
Khaoula Belhaj ◽  
Ryohei Terauchi ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Genetic Architecture ◽  
Plant Pathogens ◽  
Nucleotide Binding ◽  
Signaling Network ◽  
Signaling Networks ◽  
Leucine Rich Repeat ◽  
Nucleotide Binding Domain ◽  
Immune Signaling ◽  
Diverse Plant

Plant and animal nucleotide-binding domain and leucine-rich repeat-containing (NLR) proteins often function in pairs to mediate innate immunity to pathogens. However, the degree to which NLR proteins form signaling networks beyond genetically linked pairs is poorly understood. In this study, we discovered that a large NLR immune signaling network with a complex genetic architecture confers immunity to oomycetes, bacteria, viruses, nematodes, and insects. The network emerged over 100 million years ago from a linked NLR pair that diversified into up to one half of the NLR of asterid plants. We propose that this NLR network increases robustness of immune signaling to counteract rapidly evolving plant pathogens.

Reconstitution and structure of a plant NLR resistosome conferring immunity

Science ◽  
2019 ◽  
Vol 364 (6435) ◽  
pp. eaav5870 ◽  
Author(s):  
Jizong Wang ◽  
Meijuan Hu ◽  
Jia Wang ◽  
Jinfeng Qi ◽  
Zhifu Han ◽  
...  
Keyword(s):  
Plant Immunity ◽  
Coiled Coil ◽  
Nucleotide Binding ◽  
Leucine Rich Repeat ◽  
Nucleotide Binding Domain ◽  
Winged Helix ◽  
Pathogen Effectors ◽  
Cryo Electron Microscopy ◽  
Biochemical Mechanisms ◽  
Α Helix

Nucleotide-binding, leucine-rich repeat receptors (NLRs) perceive pathogen effectors to trigger plant immunity. Biochemical mechanisms underlying plant NLR activation have until now remained poorly understood. We reconstituted an active complex containing the Arabidopsis coiled-coil NLR ZAR1, the pseudokinase RKS1, uridylated protein kinase PBL2, and 2′-deoxyadenosine 5′-triphosphate (dATP), demonstrating the oligomerization of the complex during immune activation. The cryo–electron microscopy structure reveals a wheel-like pentameric ZAR1 resistosome. Besides the nucleotide-binding domain, the coiled-coil domain of ZAR1 also contributes to resistosome pentamerization by forming an α-helical barrel that interacts with the leucine-rich repeat and winged-helix domains. Structural remodeling and fold switching during activation release the very N-terminal amphipathic α helix of ZAR1 to form a funnel-shaped structure that is required for the plasma membrane association, cell death triggering, and disease resistance, offering clues to the biochemical function of a plant resistosome.

scholarly journals A bacterial effector protein prevents MAPK-mediated phosphorylation of SGT1 to suppress plant immunity

2019 ◽  
Author(s):  
Gang Yu ◽  
Liu Xian ◽  
Hao Xue ◽  
Wenjia Yu ◽  
Jose S. Rufian ◽  
...  
Keyword(s):  
Immune Responses ◽  
Feedback Loop ◽  
Map Kinases ◽  
Plant Immunity ◽  
Effector Protein ◽  
Leucine Rich Repeat ◽  
Nucleotide Binding Domain ◽  
Mapk Activation ◽  
Positive Feedback Loop ◽  
Shed Light

AbstractNucleotide-binding domain and leucine-rich repeat-containing (NLR) proteins function as sensors that perceive pathogen molecules and activate immunity. In plants, the accumulation and activation of NLRs is regulated by SUPPRESSOR OF G2 ALLELE OF skp1 (SGT1). In this work, we found that an effector protein named RipAC, secreted by the plant pathogen Ralstonia solanacearum, associates with SGT1 to suppress NLR-mediated SGT1-dependent immune responses, including those triggered by another R. solanacearum effector, RipE1. RipAC does not affect the accumulation of SGT1 or NLRs, or their interaction. However, RipAC inhibits the interaction between SGT1 and MAP kinases, and the phosphorylation of a MAPK target motif in the C-terminal domain of SGT1. Such phosphorylation is enhanced upon activation of immune signaling, leads to the release of the interaction between SGT1 and NLRs, and contributes to the activation of NLR-mediated responses. Additionally, SGT1 phosphorylation contributes to resistance against R. solanacearum, and this is particularly evident in the absence of RipAC. Our results shed light onto the mechanism of activation of NLR-mediated immunity, and suggest a positive feedback loop between MAPK activation and SGT1-dependent NLR activation.

scholarly journals Lessons in effector and NLR biology of plant-microbe systems

2017 ◽  
Author(s):  
Aleksandra Białas ◽  
Erin K. Zess ◽  
Juan Carlos De la Concepcion ◽  
Marina Franceschetti ◽  
Helen G. Pennington ◽  
...  
Keyword(s):  
Plant Physiology ◽  
Magnaporthe Oryzae ◽  
Rice Blast ◽  
Molecular Mechanisms ◽  
Rice Blast Fungus ◽  
Leucine Rich Repeat ◽  
Nucleotide Binding Domain ◽  
Immune Receptors ◽  
Microbe Interactions ◽  
Host Infection

A diversity of plant-associated organisms secrete effectors—proteins and metabolites that modulate plant physiology to favor host infection and colonization. However, effectors can also activate plant immune receptors, notably nucleotide-binding domain and leucine-rich repeat-containing (NLR) proteins, enabling plants to fight off invading organisms. This interplay between effectors, their host targets, and the matching immune receptors is shaped by intricate molecular mechanisms and exceptionally dynamic coevolution. In this article, we focus on three effectors, AVR-Pik, AVR-Pia, and AVR-Pii, from the rice blast fungus Magnaporthe oryzae (syn. Pyricularia oryzae), and their corresponding rice NLR immune receptors, Pik, Pia, and Pii, to highlight general concepts of plant-microbe interactions. We draw 12 lessons in effector and NLR biology that have emerged from studying these three little effectors and are broadly applicable to other plant-microbe systems.

scholarly journals The neuropeptide receptor NMUR-1 regulates the specificity of C. elegans innate immunity against pathogen infection

2021 ◽  
Author(s):  
Phillip Wibisono ◽  
Shawndra Wibisono ◽  
Jan Watteyne ◽  
Chia-Hui Chen ◽  
Durai Sellegounder ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Immune System ◽  
Immune Responses ◽  
Adaptive Immune System ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Immune Genes ◽  
C Elegans ◽  
Adaptive Immune ◽  
Functional Assays

A key question in current immunology is how the innate immune system generates high levels of specificity. Like most invertebrates, Caenorhabditis elegans does not have an adaptive immune system and relies solely on innate immunity to defend itself against pathogen attacks, yet it can still differentiate different pathogens and launch distinct innate immune responses. Here, we have found that functional loss of NMUR-1, a neuronal GPCR homologous to mammalian receptors for the neuropeptide neuromedin U, has diverse effects on C. elegans survival against various bacterial pathogens. Transcriptomic analyses and functional assays revealed that NMUR-1 modulates C. elegans transcription activity by regulating the expression of transcription factors, which, in turn, controls the expression of distinct immune genes in response to different pathogens. Our study has uncovered a molecular basis for the specificity of C. elegans innate immunity that could provide mechanistic insights into understanding the specificity of vertebrate innate immunity.

NLRP6 Induces Pyroptosis by Activation of Caspase-1 in Gingival Fibroblasts

2018 ◽  
Vol 97 (12) ◽  
pp. 1391-1398 ◽  
Author(s):  
W. Liu ◽  
J. Liu ◽  
W. Wang ◽  
Y. Wang ◽  
X. Ouyang
Keyword(s):  
Innate Immune ◽  
Gingival Tissue ◽  
Gingival Fibroblasts ◽  
Leucine Rich Repeat ◽  
Nucleotide Binding Domain ◽  
Commensal Bacterium ◽  
Caspase 1 ◽  
Proinflammatory Mediators ◽  
First Time ◽  
Receptor Family

NLRP6, a member of the nucleotide-binding domain, leucine-rich repeat-containing (NLR) innate immune receptor family, has been reported to participate in inflammasome formation. Activation of inflammasome triggers a caspase-1–dependent programming cell death called pyroptosis. However, whether NLRP6 induces pyroptosis has not been investigated. In this study, we showed that NLRP6 overexpression activated caspase-1 and gasdermin-D and then induced pyroptosis of human gingival fibroblasts, resulting in release of proinflammatory mediators interleukin (IL)–1β and IL-18. Moreover, NLRP6 was highly expressed in gingival tissue of periodontitis compared with healthy controls. Porphyromonas gingivalis, which is a commensal bacterium and has periodontopathic potential, induced pyroptosis of gingival fibroblasts by activation of NLRP6. Together, we, for the first time, identified that NLRP6 could induce pyroptosis of gingival fibroblasts by activation of caspase-1 and may play a role in periodontitis.

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