Mutations of deubiquitinase OTUD1 are associated with autoimmune disorders
Mutations of deubiquitinase OTUD1 are associated with autoimmune disorders
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去泛素酶 OTUD1 突变与自身免疫性疾病相关。
DOI：
10.1016/j.jaut.2018.07.019
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发表时间：
2018-11-01
影响因子：
12.8
通讯作者：
Yin, Yuxin
中科院分区：
文献类型：
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作者：
Lu, Dan;Song, Jia;Yin, Yuxin
先天免疫失调伴随着过量的干扰素产生有助于自身免疫性疾病。然而，免疫反应在自身免疫性疾病中的调节机制在很大程度上是未知的。在这里，我们确定了与多种自身免疫性疾病相关的OTUD1功能丧失突变。在炎症条件下，诱导型OTUD1作为免疫检查点并阻断rig - i样受体信号传导。作为一种去泛素酶，OTUD1直接与转录因子IRF3相互作用，去除IRF3赖氨酸98上k63连接的多泛素链，抑制IRF3核易位和转录活性。相反，OTUD1突变体通过降低OTUD1去泛素酶活性或其与IRF3的关联而削弱其对IRF3的抑制作用。此外，我们发现FOXO3信号是抗原刺激诱导OTUD1所必需的。我们的数据表明，OTUD1参与维持免疫稳态，OTUD1的功能缺失突变增强了免疫反应，并与自身免疫有关。
Dysregulation of innate immunity accompanied by excessive interferon production contributes to autoimmune disease. However, the mechanism by which the immune response is modulated in autoimmune disorders is largely unknown. Here we identified loss-of-function mutations of OTUD1 associated with multiple autoimmune diseases. Under inflammatory conditions, inducible OTUD1 acts as an immune checkpoint and blocks RIG-I-like receptors signaling. As a deubiquitinase, OTUD1 directly interacts with transcription factor IRF3 and removes the K63-linked poly-ubiquitin chains on IRF3 Lysine 98, which inhibits IRF3 nuclear translocation and transcriptional activity. In contrast, OTUD1 mutants impair its suppressive effects on IRF3 via attenuating the OTUD1 deubiquinase activity or its association with IRF3. Moreover, we found FOXO3 signaling is required for OTUD1 induction upon antigenic stimulation. Our data demonstrate that OTUD1 is involved in maintaining immune homeostasis and loss-of-function mutations of OTUD1 enhance the immune response and are associated with autoimmunity.