The membrane-associated E3 ubiquitin ligase MARCH3 downregulates the IL-6 receptor and suppresses colitis-associated carcinogenesis
The membrane-associated E3 ubiquitin ligase MARCH3 downregulates the IL-6 receptor and suppresses colitis-associated carcinogenesis
复制标题
膜相关 E3 泛素连接酶 MARCH3 下调 IL-6 受体并抑制结肠炎相关癌发生
DOI：
10.1038/s41423-021-00799-1
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发表时间：
2021-11-16
影响因子：
24.1
通讯作者：
Li, Shu
中科院分区：
文献类型：
--
作者：
Lin, Heng;Feng, Lu;Li, Shu
IL-6-STAT3轴在炎症相关癌变(IAC)中起重要作用。这个轴是如何被调节来调节IAC的，目前尚不清楚。在这里，我们证明了质膜相关的E3泛素连接酶MARCH3负性调节IL-6以及另一个IL-6亚家族成员OSM(OSM)触发的STAT3激活。MARCH3与IL-6受体α链(IL-6Rα)及其辅助受体gp130相关。生化实验表明，MARCH3介导了IL-6刺激后K401位的IL-6Rα和K849位的gp130的多泛素化，导致它们移位到溶酶体并在溶酶体中降解。MARCH3缺乏增加了IL-6和OSM触发的STAT3的激活和不同类型细胞中下游效应基因的诱导。MARCH3缺乏增强了葡聚糖硫酸钠(DSS)诱导的STAT3激活，增加了炎性细胞因子的表达，加重了结肠炎，以及AOM/DSS诱导的结肠炎相关癌症。此外，MARCH3在人类结直肠癌组织中表达下调，并与不同癌症类型的低生存率有关。我们的发现表明，MARCH3是IL-6诱导的STAT3激活、炎症和炎症相关癌变的关键负调控因子。
The IL-6-STAT3 axis is critically involved in inflammation-associated carcinogenesis (IAC). How this axis is regulated to modulate IAC remains unknown. Here, we show that the plasma membrane-associated E3 ubiquitin ligase MARCH3 negatively regulates STAT3 activation triggered by IL-6, as well as another IL-6 subfamily member, Oncostatin M (OSM). MARCH3 is associated with the IL-6 receptor α-chain (IL-6Rα) and its coreceptor gp130. Biochemical experiments indicated that MARCH3 mediates the polyubiquitination of IL-6Rα at K401 and gp130 at K849 following IL-6 stimulation, leading to their translocation to and degradation in lysosomes. MARCH3 deficiency increases IL-6- and OSM-triggered activation of STAT3 and induction of downstream effector genes in various cell types. MARCH3 deficiency enhances dextran sulfate sodium (DSS)-induced STAT3 activation, increases the expression of inflammatory cytokines, and exacerbates colitis, as well as azoxymethane (AOM)/DSS-induced colitis-associated cancer in mice. In addition, MARCH3 is downregulated in human colorectal cancer tissues and associated with poor survival across different cancer types. Our findings suggest that MARCH3 is a pivotal negative regulator of IL-6-induced STAT3 activation, inflammation, and inflammation-associated carcinogenesis.