USP22 suppresses the NLRP3 inflammasome by degrading NLRP3 via ATG5-dependent autophagy
USP22 suppresses the NLRP3 inflammasome by degrading NLRP3 via ATG5-dependent autophagy
复制标题
USP22 通过 ATG5 依赖性自噬降解 NLRP3，从而抑制 NLRP3 炎症小体
DOI：
10.1080/15548627.2022.2107314
复制
发表时间：
2022-08-07
期刊：
影响因子：
13.3
通讯作者：
Chen, Weilin
中科院分区：
文献类型：
--
作者：
Di, Qianqian;Zhao, Xibao;Chen, Weilin
NLRP3炎性小体参与多种炎症性疾病。为了防止过度炎症，必须严格调节炎症小体的激活，而据报道，蛋白质泛素化系统是调节炎症小体激活的方式之一。然而，炎性小体活化的去泛素化调控机制仍不明确。在这里，我们证明了USP22（泛素特异性肽酶22）促进NLRP3降解并抑制NLRP3炎性体的激活。USP22缺乏或体内沉默显著增加铝诱导的腹膜炎和脂多糖诱导的全身性炎症。在机制上，USP22通过促进atg5介导的巨噬/自噬来抑制NLRP3炎性体的激活。USP22通过降低ATG5在Lys118位点的K27-和k48连接的泛素化来稳定ATG5。综上所述，这些发现揭示了USP22在调节NLRP3炎性小体激活中的作用，并提示了治疗NLRP3炎性小体相关疾病的潜在治疗靶点。缩写:ATG5:自噬相关5;ATP：三磷酸腺苷；CASP1: caspase 1；il - 18：白细胞介素18；il - 1b /IL-1β：白细胞介素1β；有限合伙人:脂多糖;NLRC4: NLR族，CARD域包含4；NLRP3: NLR家族，含pyrin结构域3；PYCARD/ASC：包含PYD和CARD域；TNF/TNF-α：肿瘤坏死因子；USP22：泛素特异性肽酶
ABSTRACT The NLRP3 inflammasome is involved in a diverse range of inflammatory diseases. The activation of inflammasomes must be tightly regulated to prevent excessive inflammation, and the protein ubiquitination system is reported to be one of the ways in which inflammasome activation is regulated. However, the deubiquitination regulatory mechanisms of inflammasome activation remain elusive. Here, we demonstrated that USP22 (ubiquitin specific peptidase 22) promotes NLRP3 degradation and inhibits NLRP3 inflammasome activation. USP22 deficiency or in vivo silencing significantly increases alum-induced peritonitis and lipopolysaccharide-induced systemic inflammation. Mechanistically, USP22 inhibits NLRP3 inflammasome activation via the promotion of ATG5-mediated macroautophagy/autophagy. USP22 stabilizes ATG5 via decreasing K27- and K48-linked ubiquitination of ATG5 at the Lys118 site. Taken together, these findings reveal the role USP22 plays in the regulation of NLRP3 inflammasome activation and suggest a potential therapeutic target to treat NLRP3 inflammasome-related diseases. Abbreviations: ATG5: autophagy related 5; ATP: adenosine triphosphate; CASP1: caspase 1; IL18: interleukin 18; IL1B/IL-1β: interleukin 1 beta; LPS: lipopolysaccharide; NLRC4: NLR family, CARD domain containing 4; NLRP3: NLR family, pyrin domain containing 3; PYCARD/ASC: PYD and CARD domain containing; TNF/TNF-α: tumor necrosis factor; USP22: ubiquitin specific peptidase 22.