Department of Biological Sciences, Sungkyunkwan University, Suwon 16419, Republic of Korea.
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; SRC Center for Immune Research on Non-lymphoid Organs, Sungkyunkwan University, Suwon 16419, Republic of Korea.
Cell Rep. 2024 Feb 27;43(2):113752. doi: 10.1016/j.celrep.2024.113752. Epub 2024 Feb 10.
We here demonstrate that SERTAD1 is an adaptor protein responsible for the regulation of lysine 63 (K63)-linked NLRP3 polyubiquitination by the Cullin1 E3 ubiquitin ligase upon inflammasome activation. SERTAD1 specifically binds to NLRP3 but not to other inflammasome sensors. This endogenous interaction increases after inflammasome activation, interfering with the interaction between NLRP3 and Cullin1. Interleukin (IL)-1β and IL-18 secretion, as well as the cleavage of gasdermin D, are decreased in SERTAD1 knockout bone-marrow-derived macrophages, together with reduced formation of the NLRP3 inflammasome complex. Additionally, SERTAD1-deficient mice show attenuated severity of monosodium-uric-acid-induced peritonitis and experimental autoimmune encephalomyelitis. Analysis of public datasets indicates that expression of SERTAD1 mRNA is significantly increased in the patients of autoimmune diseases. Thus, our findings uncover a function of SERTAD1 that specifically reduces Cullin1-mediated NLRP3 polyubiquitination via direct binding to NLRP3, eventually acting as a crucial factor to regulate the initiation of NLRP3-mediated inflammasome activation.
我们在此证明，SERTAD1 是一种衔接蛋白，负责调节 Cullin1 E3 泛素连接酶对炎症小体激活时赖氨酸 63（K63）连接的 NLRP3 多泛素化。SERTAD1 特异性结合 NLRP3，但不结合其他炎症小体传感器。这种内源性相互作用在炎症小体激活后增加，干扰 NLRP3 和 Cullin1 之间的相互作用。SERTAD1 敲除骨髓来源的巨噬细胞中白细胞介素 (IL)-1β 和 IL-18 的分泌以及天冬氨酸特异性半胱氨酸蛋白酶 1（caspase-1）切割的 Gasdermin D 减少，同时 NLRP3 炎症小体复合物的形成减少。此外，SERTAD1 缺陷小鼠表现出减轻的单钠尿酸盐诱导的腹膜炎和实验性自身免疫性脑脊髓炎的严重程度。对公共数据集的分析表明，自身免疫性疾病患者的 SERTAD1 mRNA 表达显著增加。因此，我们的发现揭示了 SERTAD1 的一个功能，即通过直接与 NLRP3 结合，特异性降低 Cullin1 介导的 NLRP3 多泛素化，最终作为调节 NLRP3 介导的炎症小体激活起始的关键因素。
