Cullin1 binds and promotes NLRP3 ubiquitination to repress systematic inflammasome activation
Cullin1 binds and promotes NLRP3 ubiquitination to repress systematic inflammasome activation
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DOI：
10.1096/fj.201801681r
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发表时间：
2019-01
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影响因子：
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通讯作者：
Pinjun Wan;Qi Zhang;Weiyong Liu;Yaling Jia;Sha Ai;Tianci Wang;Wenbiao Wang;Pan Pan-Pan;Ge Yang;Qi Xiang;Siyu Huang;Qingyu Yang;Wei Zhang;F. Liu;Q. Tan;Wen Zhang;Kailang Wu;Yingle Liu;Jianguo Wu
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作者：
Pinjun Wan;Qi Zhang;Weiyong Liu;Yaling Jia;Sha Ai;Tianci Wang;Wenbiao Wang;Pan Pan-Pan;Ge Yang;Qi Xiang;Siyu Huang;Qingyu Yang;Wei Zhang;F. Liu;Q. Tan;Wen Zhang;Kailang Wu;Yingle Liu;Jianguo Wu
NACHT、富含亮氨酸重复序列和含有热蛋白结构域的蛋白 3（统称为 NLRP3）炎症小体的激活在宿主免疫反应中发挥着关键作用，宿主免疫反应是抵御细胞应激和病原体感染的第一道防线。然而，过度的炎症小体激活会损害宿主细胞，因此必须对其进行精确控制。在这里，我们发现 Cullin1 (CUL1) 是 Skp1-Cullin1-F-box E3 连接酶的关键成分，在控制 NLRP3 炎症小体中发挥着关键作用。 CUL1 抑制培养细胞中的炎症小体组装，抑制人单核细胞系巨噬细胞中的 NLRP3 功能，并减弱小鼠模型中的炎症反应。详细研究表明，CUL1 与 NLRP3 相互作用，促进 NLRP3 泛素化，但不促进蛋白质降解，从而抑制 NLRP3 炎性体激活。此外，在炎症刺激（包括 ATP 和尼日利亚菌素治疗）下，CUL1 与 NLRP3 解离，释放对 NLRP3 炎症小体的抑制。因此，这项研究揭示了控制 NLRP3 炎症小体系统激活的独特机制。—Wan, P.、Zhang, Q.、Liu, W.、Jia, Y.、Ai, S.、Wang, T.、Wang, W.、Pan, P.、Yang, G.、Xiang, Q.、Huang, S.、Yang, Q.、Zhang, W.、Liu, F.、Tan, Q.、Zhang, W.、Wu, K.、Liu, Y., Wu, J. Cullin1 结合并促进 NLRP3 泛素化，以抑制系统性炎症小体激活。 FASEB J. 33, 5793–5807 (2019)。 www.fasebj.org
Activation of the NACHT, leucine‐rich repeat, and pyrin domains‐containing protein 3 (collectively known as NLRP3) inflammasome plays a key role in host immune response, which is the first line of defense against cellular stresses and pathogen infections. However, excessive inflammasome activation damages host cells, and therefore it must be precisely controlled. Here, we discover that Cullin1 (CUL1), a key component of the Skp1‐Cullin1‐F‐box E3 ligase, plays a critical role in controlling the NLRP3 inflammasome. CUL1 represses inflammasome assembly in cultured cells, suppresses NLRP3 function in human monocytic cell line macrophages, and attenuates inflammatory responses in mouse model. Detailed studies demonstrate that CUL1 interacts with NLRP3 and promotes NLRP3 ubiquitination, but not protein degradation, to repress the NLRP3 inflammasome activation. Moreover, upon inflammatory stimuli, including ATP and nigericin treatments, CUL1 disassociates from NLRP3 to release the repression of the NLRP3 inflammasome. Thus, this study reveals a distinct and unique mechanism underlying the control of systematic activation of the NLRP3 inflammasome.—Wan, P., Zhang, Q., Liu, W., Jia, Y., Ai, S., Wang, T., Wang, W., Pan, P., Yang, G., Xiang, Q., Huang, S., Yang, Q., Zhang, W., Liu, F., Tan, Q., Zhang, W., Wu, K., Liu, Y., Wu, J. Cullin1 binds and promotes NLRP3 ubiquitination to repress systematic inflammasome activation. FASEB J. 33, 5793–5807 (2019). www.fasebj.org