Rhbdd3 controls autoimmunity by suppressing the production of IL-6 by dendritic cells via K27-linked ubiquitination of the regulator NEMO
Rhbdd3 controls autoimmunity by suppressing the production of IL-6 by dendritic cells via K27-linked ubiquitination of the regulator NEMO
复制标题
Rhbdd3 通过调节器 NEMO 的 K27 连接泛素化抑制树突状细胞产生 IL-6 来控制自身免疫
DOI：
10.1038/ni.2898
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发表时间：
2014-07-01
影响因子：
30.5
通讯作者：
Cao, Xuetao
中科院分区：
文献类型：
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作者：
Liu, Juan;Han, Chaofeng;Cao, Xuetao
树突状细胞（DC）的过度激活会导致自身免疫性和炎症性疾病的发生，这促使人们寻找DC激活的调节因子。在这里，我们报告，Rhbdd 3，菱形蛋白酶家族的成员，抑制激活的DC和生产的白细胞介素6（IL-6）触发的Toll样受体（TLR）。Rhbdd 3缺陷小鼠自发地发展自身免疫性疾病，其特征在于辅助性T细胞的TH 17亚群的丰度增加和由于来自DC的IL-6的增加而导致的调节性T细胞的数量减少。Rhbdd 3通过内体中的泛素结合结合（乌巴）结构域与调节剂NEMO（IKKγ）的Lys 302上的Lys 27（K27）连接的多聚泛素链直接结合。Rhbdd 3通过Lys 268上K27连接的多聚泛素链进一步募集去泛素化酶A20，以抑制K63连接的NEMO的多聚泛素化，从而抑制DC中转录因子NF-κB的活化。我们的数据确定Rhbdd 3作为DC激活的关键调节因子，并表明K27连接的多聚泛素化是一种参与自身免疫控制的有效泛素连接模式。
Excessive activation of dendritic cells (DCs) leads to the development of autoimmune and inflammatory diseases, which has prompted a search for regulators of DC activation. Here we report that Rhbdd3, a member of the rhomboid family of proteases, suppressed the activation of DCs and production of interleukin 6 (IL-6) triggered by Toll-like receptors (TLRs). Rhbdd3-deficient mice spontaneously developed autoimmune diseases characterized by an increased abundance of the TH17 subset of helper T cells and decreased number of regulatory T cells due to the increase in IL-6 from DCs. Rhbdd3 directly bound to Lys27 (K27)-linked polyubiquitin chains on Lys302 of the modulator NEMO (IKKγ) via the ubiquitin-binding–association (UBA) domain in endosomes. Rhbdd3 further recruited the deubiquitinase A20 via K27-linked polyubiquitin chains on Lys268 to inhibit K63-linked polyubiquitination of NEMO and thus suppressed activation of the transcription factor NF-κB in DCs. Our data identify Rhbdd3 as a critical regulator of DC activation and indicate K27-linked polyubiquitination is a potent ubiquitin-linked pattern involved in the control of autoimmunity.