OTUD7B deubiquitinates SQSTM1/p62 and promotes IRF3 degradation to regulate antiviral immunity
OTUD7B deubiquitinates SQSTM1/p62 and promotes IRF3 degradation to regulate antiviral immunity
复制标题
OTUD7B 去泛素化 SQSTM1/p62 并促进 IRF3 降解以调节抗病毒免疫
DOI：
10.1080/15548627.2022.2026098
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发表时间：
2022-02-02
期刊：
影响因子：
13.3
通讯作者：
Cui, Jun
中科院分区：
文献类型：
--
作者：
Xie, Weihong;Tian, Shuo;Cui, Jun
摘要去泛素化在调节巨自噬/自噬与先天免疫信号转导之间的相互作用中起着重要作用，但其调节机制尚不完全清楚。在这里，我们确定去泛素化酶OTUD 7 B作为抗病毒免疫的负调节因子，通过靶向IRF 3（干扰素调节因子3）进行选择性自噬降解。在机制上，OTUD 7 B与IRF 3相互作用，并通过在赖氨酸7（K7）处去除其K63连接的多聚泛素链以增强SQSTM 1寡聚化来激活IRF 3相关货物受体SQSTM 1/p62（隔离体1）。此外，病毒感染增加了OTUD 7 B的表达，OTUD 7 B通过促进IRF 3降解以平衡I型干扰素（IFN）信号传导而形成负反馈环。总之，我们的研究揭示了OTUD 7 B在以底物依赖性方式介导货物受体活化中的特定作用，这可能是对抗过度免疫应答的潜在靶标。缩略语：Baf A1：巴弗洛霉素A1; CGAS：环GMP-AMP合酶; DDX58/RIG-I：DExD/H-box解旋酶58; DSS：葡聚糖硫酸钠; DUBs：去泛素化酶; GFP：绿色荧光蛋白; IFN：干扰素; IKKi：IKBKB/IkappaB激酶抑制剂; IRF 3：干扰素调节因子3; ISGs：干扰素刺激基因; MAVS：线粒体抗病毒信号蛋白; MOI：感染复数; PAMP：病原体相关分子模式; SeV：仙台病毒; siRNA：小干扰RNA; SQSTM 1/p62：数据类型隔离体1; STING 1：干扰素应答刺激剂cGAMP相互作用物1; TBK 1：TANK结合激酶1; Ub：泛素; WT：野生型; VSV：水疱性口炎病毒。
ABSTRACT Deubiquitination plays an important role in the regulation of the crosstalk between macroautophagy/autophagy and innate immune signaling, yet its regulatory mechanisms are not fully understood. Here we identify the deubiquitinase OTUD7B as a negative regulator of antiviral immunity by targeting IRF3 (interferon regulatory factor 3) for selective autophagic degradation. Mechanistically, OTUD7B interacts with IRF3, and activates IRF3-associated cargo receptor SQSTM1/p62 (sequestosome 1) by removing its K63-linked poly-ubiquitin chains at lysine 7 (K7) to enhance SQSTM1 oligomerization. Moreover, viral infection increased the expression of OTUD7B, which forms a negative feedback loop by promoting IRF3 degradation to balance type I interferon (IFN) signaling. Taken together, our study reveals a specific role of OTUD7B in mediating the activation of cargo receptors in a substrate-dependent manner, which could be a potential target against excessive immune responses. Abbreviations: Baf A1: bafilomycin A1; CGAS: cyclic GMP-AMP synthase; DDX58/RIG-I: DExD/H-box helicase 58; DSS: dextran sodium sulfate; DUBs: deubiquitinating enzymes; GFP: green fluorescent protein; IFN: interferon; IKKi: IKBKB/IkappaB kinase inhibitor; IRF3: interferon regulatory factor 3; ISGs: interferon-stimulated genes; MAVS: mitochondrial antiviral signaling protein; MOI: multiplicity of infection; PAMPs: pathogen-associated molecular patterns; SeV: Sendai virus; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; Ub: ubiquitin; WT: wild-type; VSV: vesicular stomatitis virus.