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.

中文翻译：

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RNF125 和 Cbl-b 对 NLRP3 的连续泛素化限制了炎性体激活和内毒素血症

异常的 NLRP3 炎性体激活会导致内毒素血症的发生。NLRP3 炎症小体负调控的重要性仍然知之甚少。在这里，我们证明 E3 泛素连接酶 Cbl-b 对于通过 caspase-11/NLRP3 依赖的方式预防亚致死剂量的 LPS 诱导的内毒素血症至关重要。进一步的研究表明，NLRP3 经历 K63 和 K48 连接的多聚泛素化。Cbl-b 通过其泛素相关区 (UBA) 与连接到 NLRP3 富含亮氨酸重复结构域 (LRR) 的 K63 泛素链结合，然后将 NLRP3 的 K496 定位为目标，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 是另一种 E3 泛素连接酶，可启动 NLRP3 LRR 结构域的 K63 连接泛素化。因此，NLRP3 依次被 K63 和 K48 连接的泛素化所泛素化，从而保持 NLRP3 炎症小体的检查并抑制内毒素血症。