NLRP3 Phosphorylation Is an Essential Priming Event for Inflammasome Activation

Song, Nan; Liu, Zhao-Shan; Xue, Wei; Bai, Zhaofang; Wang, Qianyi; Dai, Jiang; Liu, Xin; Huang, Yanhong; Cai, Hong; Zhan, Xiaoyan; Han, Qin; Wang, Hongxia; Chen, Yuan; Li, Huiyan; Li, Ailing; Zhang, Xuemin; Zhou, Tao; Li, Tao

doi:10.1016/j.molcel.2017.08.017

Cited by 343 publications

(269 citation statements)

References 61 publications

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“…It was reported that the phosphorylation site of NLRP3 is Ser 198 , 16 which is close to the SUMO1 modification site Lys 204 . It is not known how SENP3 selectively functions in the resting and activated NLRP3 inflammasome.…”

Section: Senp3 Desumoylates Nlrp3 To Attenuate the Inflammasome Actmentioning

confidence: 97%

“…The NLRP3 inflammasome activation is regulated by phosphorylation, 16 ubiquitination, 17,43 and SUMOylation. The NLRP3 inflammasome activation is regulated by phosphorylation, 16 ubiquitination, 17,43 and SUMOylation.…”

Section: Senp3 Desumoylates Nlrp3 To Attenuate the Inflammasome Actmentioning

confidence: 99%

“…9 The inflammasome serves as a scaffold to promote the auto-catalytic cleavage of pro-Casp-1 into Casp-1, which in turn facilitates the secretion of pro-inflammatory cytokines, interleukin-1β (IL-1β) and IL-18. 15 Posttranslational modifications play key roles in the regulation of NLRP3 inflammasome activation, including phosphorylation, 16 ubiquitination, 17,18 and SUMOylation. 14 However, aberrant inflammasome activation may cause deleterious inflammation and various inflammatory diseases.…”

Section: Introductionmentioning

confidence: 99%

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SUMO1 SUMOylates and SENP3 deSUMOylates NLRP3 to orchestrate the inflammasome activation

et al. 2019

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contributed equally to this work.Abbreviations: AIM2, absent in melanoma 2; ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; BMDM, bone marrow-derived macrophage; Casp-1, caspase-1; FITC, fluorescein isothiocyanate; GAPDH, glyceraldehyde 3-phosphate; HEK293T, human embryonic kidney cell line; IL-1β, interleukin-1β; LDH, lactate dehydrogenase; LRR, leucine-rich repeat; NACHT, NAIP (neuronal apoptosis inhibitory protein), CIITA (MHC class II transcription activator), HET-E (incompatibility locus protein from Podospora anserina) and TP1 (telomerase-associated protein); NLRP3, NACHT, LRR, and PYD domains-containing protein 3; PYD, pyrin domain; SENP, SUMO-specific protease; shRNA, short hairpin RNA; SUMO, small ubiquitin-like modifier; TCA, trichloroacetic acid solution; THP-1, human monocytic cell line; TPA, phorbol-12-myristate-13-acetate; UBC9, ubiquitin-like conjugating enzyme 9. AbstractThe NLRP3 inflammasome regulates innate immune and inflammatory responses by promoting caspase1-dependent induction of pro-inflammatory cytokines. However, aberrant inflammasome activation causes diverse diseases, and thus inflammasome activity must be tightly controlled. Here, we reveal a molecular mechanism underlying the regulation of NLRP3 inflammasome. NLRP3 interacts with SUMO-conjugating enzyme (UBC9), which subsequently promotes small ubiquitin-like modifier 1 (SUMO1) to catalyze NLRP3 SUMOylation at residue Lys 204 . SUMO1-catalyzed SUMOylation of NLRP3 facilitates ASC oligomerization, inflammasome activation, and interleukin-1β secretion. Moreover, this study also reveals that SUMO-specific protease 3 (SENP3) is required for the deSUMOylation of NLRP3. Interestingly, SENP3 deSUMOylates NLRP3 to attenuate ASC recruitment and speck formation, the NLRP3 inflammasome activation, as well as IL-1β cleavage and secretion. In conclusion, we reveal that SUMO1-catalyzed SUMOylation and SENP3-mediated deSUMOylation of NLRP3 orchestrate the inflammasome activation. K E Y W O R D Sinflammasome, innate immune response, interleukin-1β, posttranslational modification, SUMO1catalyzed SUMOylation 1498 | SHAO et Al.

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Section: Senp3 Desumoylates Nlrp3 To Attenuate the Inflammasome Actmentioning

confidence: 97%

Section: Senp3 Desumoylates Nlrp3 To Attenuate the Inflammasome Actmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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SUMO1 SUMOylates and SENP3 deSUMOylates NLRP3 to orchestrate the inflammasome activation

et al. 2019

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“…It has recently been reported that JNK1-mediated NLRP3 phosphorylation at S194 is a critical priming event during NLRP3 inflammasome activation and NLRP3 S194A mutant exhibits a higher level of ubiquitination (Song et al, 2017). It has recently been reported that JNK1-mediated NLRP3 phosphorylation at S194 is a critical priming event during NLRP3 inflammasome activation and NLRP3 S194A mutant exhibits a higher level of ubiquitination (Song et al, 2017).…”

Section: Phosphorylation Of Serine 194 In Nlrp3 Modulates Its Interacmentioning

confidence: 99%

ABRO1 promotes NLRP3 inflammasome activation through regulation of NLRP3 deubiquitination

et al. 2019

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Deubiquitination of NLRP3 has been suggested to contribute to inflammasome activation, but the roles and molecular mechanisms are still unclear. We here demonstrate that ABRO1, a subunit of the BRISC deubiquitinase complex, is necessary for optimal NLRP3‐ASC complex formation, ASC oligomerization, caspase‐1 activation, and IL‐1β and IL‐18 production upon treatment with NLRP3 ligands after the priming step, indicating that efficient NLRP3 activation requires ABRO1. Moreover, we report that ABRO1 deficiency results in a remarkable attenuation in the syndrome severity of NLRP3‐associated inflammatory diseases, including MSU‐ and Alum‐induced peritonitis and LPS‐induced sepsis in mice. Mechanistic studies reveal that LPS priming induces ABRO1 binding to NLRP3 in an S194 phosphorylation‐dependent manner, subsequently recruiting the BRISC to remove K63‐linked ubiquitin chains of NLRP3 upon stimulation with activators. Furthermore, deficiency of BRCC3, the catalytically active component of BRISC, displays similar phenotypes to ABRO1 knockout mice. Our findings reveal an ABRO1‐mediated regulatory signaling system that controls activation of the NLRP3 inflammasome and provide novel potential targets for treating NLRP3‐associated inflammatory diseases.

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“…L'impact respectif de ces différentes voies in vivo en contexte infectieux ou auto-inflammatoire, reste cependant encore mal compris. pour origine les voies de signalisation impliquant MyD88 et/ou TRIF, et sa cinétique peut être reliée au priming de NLRP3 par ces voies [33]. Cette phosphorylation induit une déubiquitination de NLRP3, et semble favoriser son oligomérisation.…”

Section: Les Voies De Signalisation Qui Contrôlent L'assemblage De L'unclassified

NLRP3, un inflammasome sous contrôle

Groslambert

2018

Med Sci (Paris)

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> La réponse immunitaire innée protège l'organisme par la détection rapide des agents pathogènes et des lésions via des récepteurs spéciali-sés, dont NLRP3. Celui-ci assemble un inflammasome, un complexe cytosolique de signalisation qui active la caspase-1, contrôle la libération de cytokines et de facteurs inflammatoires produits dans le cytosol comme les interleukines 1 / . Les pathologies inflammatoires associées à NLRP3, dont la goutte, révèlent la nécessité d'un contrôle étroit de son activité. Cette revue présente les avancées sur la signalisation du priming (ou amorçage) du complexe puis de son activation avec une attention particulière sur le rôle des modifications post-traductionnelles de NLRP3. < cytokines et d'autres facteurs intracellulaires pro-inflammatoires dont l'IL-1 La mort par pyroptose de cellules infectées permet d'éliminer en parallèle les niches de réplication des pathogènes intracellulaires. La structure des inflammasomes dits non-canoniques, associés à la caspase-11, ou 4 et 5 chez l'homme, reste mal connue. Les inflammasomes canoniques, qui sont eux, associés à la caspase-1, sont assemblés par des récepteurs cytosoliques de la famille des NLR (nucleotide-binding domain leucin-rich repeat) ou ALR (Aim2-like receptors). Ces récepteurs s'oligomérisent pour former une plateforme de nucléation pour des filaments formés par la protéine adaptatrice ASC (apoptosis-associated speck-like protein containing a CARD domain, aussi appelé PYCARD, CARD5, TMS1, Q9ULZ3), dont la surface permet, à son tour, la nucléation de filaments de pro-caspase-1 [4]. Ces inflammasomes forment des specks (ou structures ponctiformes) d'une taille de l'ordre du micron, visibles en microscopie, et qui sont uniques pour une cellule. NLRP3 (nucleotide-binding domain leucin-rich repeat [LRR] and pyrin-containing receptor 3, nommé également cryopyrin, CIAS1 [cold autoinflammatory syndrome 1 protein] ou NALP3 [NACHT, LRR and PYD domains-containing protein 3]) a été initialement décrit pour son association génétique avec des syndromes auto-inflammatoires héréditaires monogéniques dominants, nommés CAPS (cryopyrin-associated periodic syndrome) ou cryopyrinopathies [5]. Depuis, NLRP3 a été impliqué dans de nombreuses pathologies multifactorielles à composante inflammatoire, dont l'arthrite goutteuse, l'athérosclérose, le diabète de type 2 et la stéatose hépatique non-alcoolique [6,7]. Il est également impliqué dans plusieurs maladies neurodégénéra-tives, dont la sclérose en plaques et les maladies d'Alzheimer et de Parkinson, ainsi que dans les pathologies associées au vieillissement [6][7][8][9]. NLRP3 est aussi important au cours des infections par diffé-rents pathogènes. Il intervient en effet dans la reconnaissance de

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NLRP3 Phosphorylation Is an Essential Priming Event for Inflammasome Activation

Cited by 343 publications

References 61 publications

SUMO1 SUMOylates and SENP3 deSUMOylates NLRP3 to orchestrate the inflammasome activation

SUMO1 SUMOylates and SENP3 deSUMOylates NLRP3 to orchestrate the inflammasome activation

ABRO1 promotes NLRP3 inflammasome activation through regulation of NLRP3 deubiquitination

NLRP3, un inflammasome sous contrôle

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