MARCH3 negatively regulates IL-3-triggered inflammatory response by mediating K48-linked polyubiquitination and degradation of IL-3Rα.
MARCH3 negatively regulates IL-3-triggered inflammatory response by mediating K48-linked polyubiquitination and degradation of IL-3Rα.
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DOI：
10.1038/s41392-021-00834-7
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发表时间：
2022-01-24
影响因子：
39.3
通讯作者：
Li S
中科院分区：
文献类型：
--
作者：
Feng L;Li C;Zeng LW;Gao D;Sun YH;Zhong L;Lin H;Shu HB;Li S
白介素3(IL-3)是一种造血生长因子，也是脓毒症等炎症反应的重要调节因子。IL-3与IL-3受体α(IL-3Rα)结合，IL-3Rβ与IL-3Rβ结合启动信号转导。IL-3触发的生理和病理效应是如何在受体水平上调节的，目前尚不清楚。在这里，我们表明，质膜相关的E3泛素连接酶MARCH3负调控IL-3触发的信号转导。MARCH3与IL-3Rα结合，在K377处介导其K48连锁的多泛素化，促进其蛋白酶体降解。MARCH3缺乏促进IL-3触发的下游效应基因的转录和IL-3诱导的髓系细胞的扩张。在盲肠结扎穿孔(CLP)脓毒症模型中，MARCH3缺乏加重了炎性细胞因子IL-3的表达，器官损伤和炎症性死亡。我们的研究结果表明，MARCH3对IL-3Rα的调节在IL-3触发的生理功能和炎症性疾病中起重要作用。
Interleukin-3 (IL-3) is a hematopoietic growth factor and critical regulator of inflammatory response such as sepsis. IL-3 binds to IL-3 receptor α (IL-3Rα), which is then associated with IL-3Rβ to initiate signaling. How IL-3-triggered physiological and pathological effects are regulated at the receptor level is unclear. Here, we show that the plasma membrane-associated E3 ubiquitin ligase MARCH3 negatively regulates IL-3-triggered signaling. MARCH3 is associated with IL-3Rα, mediates its K48-linked polyubiquitination at K377 and promotes its proteasomal degradation. MARCH3-deficiency promotes IL-3-triggered transcription of downstream effector genes and IL-3-induced expansion of myeloid cells. In the cecal ligation and puncture (CLP) model of sepsis, MARCH3-deficiency aggravates IL-3-ampified expression of inflammatory cytokines, organ damage and inflammatory death. Our findings suggest that regulation of IL-3Rα by MARCH3 plays an important role in IL-3-triggered physiological functions and inflammatory diseases.
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DOI：
10.1038/nri3552
发表时间：
2013-12
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
11.4
作者：
MUI, ALF;WAKAO, H;MIYAJIMA, A
通讯作者：
MIYAJIMA, A
影响因子：
64.8
作者：
McAlpine CS;Park J;Griciuc A;Kim E;Choi SH;Iwamoto Y;Kiss MG;Christie KA;Vinegoni C;Poller WC;Mindur JE;Chan CT;He S;Janssen H;Wong LP;Downey J;Singh S;Anzai A;Kahles F;Jorfi M;Feruglio PF;Sadreyev RI;Weissleder R;Kleinstiver BP;Nahrendorf M;Tanzi RE;Swirski FK
通讯作者：
Swirski FK
影响因子：
12.4
作者：
Chihara, T.;Suzu, S.;Okada, S.
通讯作者：
Okada, S.
影响因子：
56.9
作者：
Lin, Haishan;Lee, Ernestine;Williams, Lewis T.
通讯作者：
Williams, Lewis T.