SUMO-mediated regulation of NLRP3 modulates inflammasome activity.
SUMO-mediated regulation of NLRP3 modulates inflammasome activity.
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SUMO介导的NLRP3调节调节炎症体活性。
DOI：
10.1038/s41467-018-05321-2
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发表时间：
2018-08-01
影响因子：
16.6
通讯作者：
Meier P
中科院分区：
文献类型：
--
作者：
Barry R;John SW;Liccardi G;Tenev T;Jaco I;Chen CH;Choi J;Kasperkiewicz P;Fernandes-Alnemri T;Alnemri E;Drag M;Chen Y;Meier P
NLRP 3炎性体对感染和组织损伤做出反应，并通过激活白细胞介素（IL）-1β、IL-18和细胞凋亡导致的细胞死亡来迅速升级炎症强度。NLRP 3炎性小体如何负调控尚不清楚。在这里，我们表明，NLRP 3炎性小体激活被sumoylation抑制。NLRP 3被SUMO E3-连接酶MAPL类小泛素化，并且通过SUMO特异性蛋白酶SENP 6和SENP 7的刺激依赖性NLRP 3去小泛素化促进NLRP 3活化。通过SUMO受体赖氨酸的NLRP 3突变或MAPL的消耗，缺陷的NLRP 3 SUMO化导致增强的半胱天冬酶-1活化和IL-1β释放。相反，SENP 7的消耗抑制NLRP 3依赖性ASC寡聚化、半胱天冬酶-1活化和IL-1β释放。这些数据表明NLRP 3的SUMO化抑制炎性小体活化，并鉴定SUMO蛋白酶作为治疗炎性疾病的潜在药物靶标。NLRP 3炎性小体是炎症反应的重要组成部分，但其如何负调控仍不清楚。在这里，作者表明通过类小泛素化的NLRP 3的翻译后修饰抑制炎性小体活性，并且通过SENP 6和SENP 7蛋白酶的NLRP 3的去类小泛素化促进NLRP 3活化。
The NLRP3 inflammasome responds to infection and tissue damage, and rapidly escalates the intensity of inflammation by activating interleukin (IL)-1β, IL-18 and cell death by pyroptosis. How the NLRP3 inflammasome is negatively regulated is poorly understood. Here we show that NLRP3 inflammasome activation is suppressed by sumoylation. NLRP3 is sumoylated by the SUMO E3-ligase MAPL, and stimulation-dependent NLRP3 desumoylation by the SUMO-specific proteases SENP6 and SENP7 promotes NLRP3 activation. Defective NLRP3 sumoylation, either by NLRP3 mutation of SUMO acceptor lysines or depletion of MAPL, results in enhanced caspase-1 activation and IL-1β release. Conversely, depletion of SENP7 suppresses NLRP3-dependent ASC oligomerisation, caspase-1 activation and IL-1β release. These data indicate that sumoylation of NLRP3 restrains inflammasome activation, and identify SUMO proteases as potential drug targets for the treatment of inflammatory diseases. The NLRP3 inflammasome is an important component of inflammatory responses, but how it is negatively regulated is still unclear. Here the authors show that post-translational modification of NLRP3 by sumoylation suppresses inflammasome activity, and that desumoylation of NLRP3 by the SENP6 and SENP7 proteases promotes NLRP3 activation.
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影响因子：
4.6
作者：
Doiron K;Goyon V;Coyaud E;Rajapakse S;Raught B;McBride HM
通讯作者：
McBride HM
影响因子：
64.8
作者：
通讯作者：
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影响因子：
4.8
作者：
Lin, DH;Tatham, MH;Chen, Y
通讯作者：
Chen, Y
影响因子：
5.8
作者：
Beauclair, Guillaume;Bridier-Nahmias, Antoine;Zamborlini, Alessia
通讯作者：
Zamborlini, Alessia
影响因子：
4.8
作者：
Juliana, Christine;Fernandes-Alnemri, Teresa;Alnemri, Emad S.
通讯作者：
Alnemri, Emad S.