Spata2-CYLD去ASC线性泛素化抑制NLRP3炎症小体活化  

ASC linear deubiquitination by Spata2-CYLD inhibits NLRP3inflammasome activation

作　　者：吴丹丹 蒋小丽 张双艳 李文果 杨晓东 WU Dan-dan;JIANG Xiao-li;ZHANG Shuang-yan;LI Wen-guo;YANG Xiao-dong(Shanghai Institute of Immunology,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China)

机构地区：[1]上海交通大学医学院上海市免疫学研究所,上海200025

出　　处：《现代免疫学》2021年第4期272-277,共6页Current Immunology

基　　金：国家自然科学基金面上项目(31770818,31570770)。

摘　　要：含NACHT-LRR-PYD结构域蛋白3(NOD-like receptor family pyrin domain-containing protein 3,NLRP3)炎症小体是由NLRP3、凋亡相关斑点样蛋白(apoptosis-associated speck-like protein containing a CARD,ASC)和Caspase-1组装成的多蛋白复合物,能够诱导IL-1β的成熟与分泌,促进炎症反应发生。它的异常活化可导致多种炎症性疾病。已有研究表明,ASC线性泛素化对炎症小体活化至关重要,但是它是否受去泛素化作用调控尚不清楚。课题组最近研究显示,精子发生相关蛋白2(spermatogenesis-associated protein 2,Spata2)与圆柱瘤蛋白(cylindromatosis tumor suppressor protein,CYLD)组成的去泛素化酶复合物通过去泛素化NLRP3炎症小体上游调节蛋白Polo样蛋白激酶4(Polo-like kinases 4,PLK4)抑制炎症小体活化。研究进一步发现,Spata2-CYLD还可去除ASC的线性泛素化,并确定了泛素化位点及其对ASC活化炎症小体功能的重要性。机制研究显示Spata2-CYLD与ASC在细胞中共定位,并且通过NLRP3蛋白结合至炎症小体发挥去泛素化ASC的作用。研究首次鉴定到ASC的去泛素化酶,揭示了Spata2-CYLD调控NLRP3炎症小体活化的又一新机制,为NLRP3炎症小体活化的调控机制提供了新认识。NOD-like receptor family pyrin domain-containing protein 3(NLRP3)inflammasome is a multi-protein complex assembled by NLRP3,apoptosis-associated speck-like protein containing a CARD(ASC)and Caspase-1,which can induce the maturation and secretion of IL-1βand promote inflammation.Its abnormal activation causes a variety of inflammatory diseases.Previous studies have shown that ASC linear ubiquitination is essential for NLRP3inflammasome activation,but whether it is regulated by deubiquitination is unclear.Our recent study has revealed that the deubiquitinase complex formed by spermatogenesisassociated protein 2(Spata2)and cylindromatosis tumor suppressor protein(CYLD)inhibits inflammasome activation by deubiquitination of the NLRP3inflammasome upstream regulatory protein Polo-like kinases 4(PLK4).This study indicated that Spata2-CYLD can also deconjugate ASC linear ubiquitination,identified ASC ubiquitination sites,and revealed their importance for ASC function in activating NLRP3inflammasome.The mechanistic study demonstrated that Spata2-CYLD colocalized with ASC in HEK293cells,bounded NLRP3inflammasome by interacting with NLRP3protein complex for the ASC linear deubiquitination.Taken together,this study demonstrates Spata2-CYLD as ASC deubiquitinase for the first time,reveals a new mechanism by which Spata2-CYLD regulates the NLRP3inflammasome activation,and provides new insights into the regulation mechanism of NLRP3inflammasome activation.

关 键 词：含NACHT-LRR-PYD结构域蛋白3 凋亡相关斑点样蛋白 精子发生相关蛋白2 圆柱瘤蛋白 炎症小体 

分 类 号：R392.11[医药卫生—免疫学]