Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH.
Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
J Exp Med. 2020 Apr 6;217(4). doi: 10.1084/jem.20182091.
Aberrant NLRP3 inflammasome activation contributes to the development of endotoxemia. The importance of negative regulation of NLRP3 inflammasomes remains poorly understood. Here, we show that the E3 ubiquitin ligase Cbl-b is essential for preventing endotoxemia induced by a sub-lethal dose of LPS via a caspase-11/NLRP3-dependent manner. Further studies show that NLRP3 undergoes both K63- and K48-linked polyubiquitination. Cbl-b binds to the K63-ubiquitin chains attached to the NLRP3 leucine-rich repeat domain (LRR) via its ubiquitin-associated region (UBA) and then targets NLRP3 at K496 for K48-linked ubiquitination and proteasome-mediated degradation. We also identify RNF125 as an additional E3 ubiquitin ligase that initiates K63-linked ubiquitination of the NLRP3 LRR domain. Therefore, NLRP3 is sequentially ubiquitinated by K63- and K48-linked ubiquitination, thus keeping the NLRP3 inflammasomes in check and restraining endotoxemia.
异常的 NLRP3 炎性小体激活有助于内毒素血症的发展。NLRP3 炎性小体的负调控的重要性仍知之甚少。在这里，我们表明，E3 泛素连接酶 Cbl-b 通过半胱天冬酶-11/NLRP3 依赖性方式对于防止亚致死剂量 LPS 诱导的内毒素血症是必需的。进一步的研究表明，NLRP3 经历 K63 和 K48 连接的多泛素化。Cbl-b 通过其泛素相关区域 (UBA) 与 NLRP3 的亮氨酸丰富重复结构域 (LRR) 上的 K63-连接的泛素链结合，然后将 NLRP3 靶向 K496 进行 K48 连接的泛素化和蛋白酶体介导的降解。我们还确定 RNF125 为另一种 E3 泛素连接酶，它起始 NLRP3 LRR 结构域的 K63 连接的泛素化。因此，NLRP3 被 K63 和 K48 连接的泛素化依次泛素化，从而使 NLRP3 炎性小体保持在控制之下并抑制内毒素血症。
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