Reciprocal regulation of IL-33 receptor-mediated inflammatory response and pulmonary fibrosis by TRAF6 and USP38.
Reciprocal regulation of IL-33 receptor-mediated inflammatory response and pulmonary fibrosis by TRAF6 and USP38.
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TRAF6 和 USP38 对 IL-33 受体介导的炎症反应和肺纤维化的相互调节
DOI：
10.1073/pnas.2116279119
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发表时间：
2022-03-08
影响因子：
11.1
通讯作者：
Li S
中科院分区：
文献类型：
--
作者：
Yi XM;Li M;Chen YD;Shu HB;Li S
IL-33R介导局部炎症反应，在免疫疾病的发病机制中发挥着至关重要的作用。在这项研究中，我们鉴定了 USP38，它通过介导 K27 连接的 IL-33R 在 K511 处的去泛素化及其自噬降解来负调节 IL-33 触发的信号传导。 USP38 缺乏会加重 IL-33 诱导的肺部炎症反应和博莱霉素诱导的肺纤维化。我们进一步表明，E3 泛素连接酶 TRAF6 催化 IL-33R 在 K511 处的 K27 连接多泛素化，而 TRAF6 的缺陷会抑制 IL-33 介导的信号传导。我们的研究结果揭示了如何精确调节 IL-33R 以确保其在休息细胞中失活并在 IL-33 刺激后正确激活的重要机制。警告细胞因子白细胞介素33受体（IL-33R）介导局部炎症反应，并在肺纤维化和类风湿性关节炎等免疫疾病的发病机制中发挥关键作用。 IL-33R 是否以及如何受到调节仍然是个谜。在这里，我们确定泛素特异性蛋白酶 38 (USP38) 是 IL-33R 介导信号传导的负调节因子。 USP38 缺乏会促进白细胞介素 33 (IL-33) 诱导的体外和体内下游促炎症反应。 Usp38−/−小鼠更容易受到炎症损伤和死亡，并且在博来霉素治疗后出现更严重的肺纤维化。 USP38 与 IL-33R 组成型相关，并在 K511 处解偶联其 K27 连接的多聚泛素化，导致其自噬降解。我们进一步表明，E3 泛素连接酶肿瘤坏死因子受体相关因子 6 (TRAF6) 催化 IL-33R 在 K511 处的 K27 连接多泛素化，而 TRAF6 的缺陷会抑制 IL-33 介导的信号传导。我们的研究结果表明，TRAF6 和 USP38 对 IL-33R 的 K27 连接多泛素化和去泛素化可相互调节 IL-33R 水平和信号传导，这代表了调节 IL-33 触发的肺部炎症反应和肺纤维化的关键机制。
IL-33R mediates local inflammatory responses and plays crucial roles in the pathogenesis of immune diseases. In this study, we identified USP38, which negatively regulates IL-33-triggered signaling by mediating K27-linked deubiquitination of IL-33R at K511 and its autophagic degradation. USP38 deficiency aggravates IL-33–induced lung inflammatory response and bleomycin-induced pulmonary fibrosis. We further show that the E3 ubiquitin ligase TRAF6 catalyzes K27-linked polyubiquitination of IL-33R at K511, and that deficiency of TRAF6 inhibits IL-33–mediated signaling. Our findings reveal an important mechanism regarding how IL-33R is precisely regulated to ensure its inactivation in rest cells and proper activation following IL-33 stimulation. The warning cytokine interleukin-33 receptor (IL-33R) mediates local inflammatory responses and plays crucial roles in the pathogenesis of immune diseases such as pulmonary fibrosis and rheumatoid arthritis. Whether and how IL-33R is regulated remain enigmatic. Here, we identified ubiquitin-specific protease 38 (USP38) as a negative regulator of IL-33R–mediated signaling. USP38 deficiency promotes interleukin-33 (IL-33)–induced downstream proinflammatory responses in vitro and in vivo. Usp38−/− mice are more susceptible to inflammatory damage and death and developed more serious pulmonary fibrosis after bleomycin treatment. USP38 is constitutively associated with IL-33R and deconjugates its K27-linked polyubiquitination at K511, resulting in its autophagic degradation. We further show that the E3 ubiquitin ligase tumor necrosis factor receptor–associated factor 6 (TRAF6) catalyzes K27-linked polyubiquitination of IL-33R at K511, and that deficiency of TRAF6 inhibits IL-33–mediated signaling. Our findings suggest that K27-linked polyubiquitination and deubiquitination of IL-33R by TRAF6 and USP38 reciprocally regulate IL-33R level and signaling, which represents a critical mechanism in the regulation of IL-33–triggered lung inflammatory response and pulmonary fibrosis.
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影响因子：
5.3
作者：
Conze, Dietrich B.;Wu, Chuan-Jin;Ashwell, Jonathan D.
通讯作者：
Ashwell, Jonathan D.
影响因子：
16
作者：
Py, Benedicte F.;Kim, Mi-Sung;Yuan, Junying
通讯作者：
Yuan, Junying
影响因子：
32.4
作者：
McHedlidze T;Waldner M;Zopf S;Walker J;Rankin AL;Schuchmann M;Voehringer D;McKenzie AN;Neurath MF;Pflanz S;Wirtz S
通讯作者：
Wirtz S
抗 IL-33 抗体治疗可抑制过敏性哮喘小鼠模型的气道炎症
DOI：
10.1016/j.bbrc.2009.06.008
发表时间：
2009-08-14
影响因子：
3.1
作者：
Liu, Xiaojin;Li, Mingcai;Huang, Tian
通讯作者：
Huang, Tian
影响因子：
14.2
作者：
Barnes, Peter J.
通讯作者：
Barnes, Peter J.