The proinflammatory cytokine IL-1β plays critical roles in inflammatory and autoimmune diseases. IL-1β signaling is tightly regulated to avoid excessive inflammatory response. In this study, we identified the E3 ubiquitin ligase membrane-associated RING-CH-type finger 3 (MARCH3) as a critical negative regulator of IL-1β–triggered signaling. Overexpression of MARCH3 inhibited IL-1β–triggered activation of NF-κB as well as expression of inflammatory genes, whereas MARCH3 deficiency had the opposite effects. MARCH3-deficient mice produced higher levels of serum inflammatory cytokines and were more sensitive to inflammatory death upon IL-1β injection or Listeria monocytogenes infection. Mechanistically, MARCH3 was associated with IL-1 receptor I (IL-1RI) and mediated its K48-linked polyubiquitination at K409 and lysosomal-dependent degradation. Furthermore, IL-1β stimulation triggered dephosphorylation of MARCH3 by CDC25A and activation of its E3 ligase activity. Our findings suggest that MARCH3-mediated IL-1RI degradation is an important mechanism for attenuating IL-1β–triggered inflammatory response.

促炎细胞因子IL-1β在炎性和自身免疫性疾病中起关键作用。严格调节IL-1β信号传导以避免过度的炎症反应。在这项研究中，我们确定了E3泛素连接酶膜相关的RING-CH型手指3（MARCH3）是IL-1β触发信号的关键负调控因子。MARCH3的过表达抑制IL-1β触发的NF-κB激活以及炎性基因的表达，而MARCH3缺乏则起相反的作用。缺乏MARCH3的小鼠产生更高水平的血清炎性细胞因子，并且在注射IL-1β或单核细胞增生性李斯特菌后对炎性死亡更敏感感染。从机制上讲，MARCH3与IL-1受体I（IL-1RI）相关，并介导其在K409处与K48相连的多聚泛素化和溶酶体依赖性降解。此外，IL-1β刺激触发了CDC25A对MARCH3的去磷酸化及其E3连接酶活性的激活。我们的发现表明，MARCH3介导的IL-1RI降解是减弱IL-1β触发的炎症反应的重要机制。