MARCH3 attenuates IL-1β-triggered inflammation by mediating K48-linked polyubiquitination and degradation of IL-1RI
MARCH3 attenuates IL-1β-triggered inflammation by mediating K48-linked polyubiquitination and degradation of IL-1RI
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MARCH3 通过介导 K48 连接的多聚泛素化和 IL-1RI 的降解来减轻 IL-1 β 引发的炎症
DOI：
10.1073/pnas.1806217115
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发表时间：
2018-12-04
影响因子：
11.1
通讯作者：
Shu, Hong-Bing
中科院分区：
文献类型：
--
作者：
Lin, Heng;Gao, Deng;Shu, Hong-Bing
促炎细胞因子IL-1 β在炎症和自身免疫性疾病中起着关键作用。IL-1 β信号传导受到严格调控，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型指3（MARCH 3）作为IL-1 β触发信号的关键负调节因子。MARCH 3的过表达抑制了IL-1 β触发的NF-κ B活化以及炎症基因的表达，而MARCH 3缺乏则具有相反的作用。MARCH 3缺陷小鼠产生更高水平的血清炎性细胞因子，并且对IL-1 β注射或单核细胞增生李斯特菌感染后的炎性死亡更敏感。从机制上讲，MARCH 3与IL-1受体I（IL-1 RI）相关，并介导其K409处的K48连接的多聚泛素化和溶酶体依赖性降解。此外，IL-1 β刺激通过CDC 25 A触发MARCH 3的去磷酸化并激活其E3连接酶活性。我们的研究结果表明，MARCH 3介导的IL-1 RI降解是减弱IL-1 β触发的炎症反应的重要机制。
The proinflammatory cytokine IL-1 beta plays critical roles in inflammatory and autoimmune diseases. IL-1 beta 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-1 beta-triggered signaling. Overexpression of MARCH3 inhibited IL-1 beta-triggered activation of NF-kappa B 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-1 beta 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-1 beta 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-1 beta-triggered inflammatory response.