Selective autophagy controls the stability of transcription factor IRF3 to balance type I interferon production and immune suppression.
Selective autophagy controls the stability of transcription factor IRF3 to balance type I interferon production and immune suppression.
复制标题
选择性自噬控制转录因子 IRF3 的稳定性，以平衡 I 型干扰素的产生和免疫抑制
DOI：
10.1080/15548627.2020.1761653
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发表时间：
2020
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：
Wu Yaoxing;Jin Shouheng;Liu Qingxiang;Zhang Yu;Ma Ling;Zhao Zhiyao;Yang Shuai;Li Yi-Ping;Cui Jun
IRF3(干扰素调节因子3)是抗病毒天然免疫信号中最关键的转录因子之一，广泛表达于多种细胞中。虽然已经证明IRF3可以在病毒感染过程中激发多种细胞过程，包括产生I型干扰素，但IRF3活性的精确调控机制仍不完全清楚。在这里，我们报道了由Cargo受体CALCOCO2/NDP52介导的选择性巨型自噬/自噬以病毒载量依赖的方式促进IRF3的降解。去泛素酶PSMD14/POH1通过切割IRF3上K27连接的赖氨酸313位多泛素链来维持其基础水平和I型干扰素的激活，从而防止IRF3的自噬降解。由PSMD14或CALCOCO2介导的IRF3的自噬降解确保了对IRF3活性的精确控制，并微调了针对病毒感染的免疫反应。我们的研究揭示了PSMD14在平衡以IRF3为中心的干扰素激活和免疫抑制方面的调节作用，并为选择性自噬和I型干扰素信号之间的串扰提供了见解。缩写：ATG5：自噬相关基因5；Baf A1：Bafilmycin A1；BECN1：Beclin 1；CALCOCO2/NDP52：钙结合和螺旋线圈结构域2；cGAS：环状GMP-AMP合成酶；DDX58/RIG-I：DExd/H-box解旋酶58；DUBS：去泛素酶；干扰素：on；IRF3：干扰素调节因子3；Mavs：抗病毒信号转导蛋白；MOI：感染的多样性；PAMPs：病原体相关的分子模式；PBMC：外周血单核细胞；PSMD14/POH1：蛋白酶体26S亚单位，非ATPase 14；RIPA：RLR诱导的IRF3介导的细胞凋亡途径；SeV：仙台病毒；SQSTM1/p62：隔离小体1；STING1：干扰素反应刺激因子cGAMP相互作用蛋白1；TBK1：坦克结合激酶1；Ub：泛素；WT：野生型
IRF3 (interferon regulatory factor 3) is one of the most critical transcription factors in antiviral innate immune signaling, which is ubiquitously expressed in a variety of cells. Although it has been demonstrated that IRF3 can provoke multiple cellular processes during viral infection, including type I interferon (IFN) production, the mechanisms underlying the precise regulation of IRF3 activity are still not completely understood. Here, we report that selective macroautophagy/autophagy mediated by cargo receptor CALCOCO2/NDP52 promotes the degradation of IRF3 in a virus load-dependent manner. Deubiquitinase PSMD14/POH1 prevents IRF3 from autophagic degradation by cleaving the K27-linked poly-ubiquitin chains at lysine 313 on IRF3 to maintain its basal level and IRF3-mediated type I IFN activation. The autophagic degradation of IRF3 mediated by PSMD14 or CALCOCO2 ensures the precise control of IRF3 activity and fine-tunes the immune response against viral infection. Our study reveals the regulatory role of PSMD14 in balancing IRF3-centered IFN activation with immune suppression and provides insights into the crosstalk between selective autophagy and type I IFN signaling.Abbreviations:ATG5: autophagy related gene 5; Baf A1: bafilomycin A1; BECN1: beclin 1; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CGAS: cyclic GMP-AMP synthase; DDX58/RIG-I: DExD/H-box helicase 58; DUBs: deubiquitinating enzymes; IFN: interferon; IRF3: interferon regulatory factor 3; MAVS: mitochondrial antiviral signaling protein; MOI: multiplicity of infection; PAMPs: pathogen-associated molecule patterns; PBMC: peripheral blood mononuclear cell; PSMD14/POH1: proteasome 26S subunit, non-ATPase 14; RIPA: RLR-induced IRF3-mediated pathway of apoptosis; SeV: Sendai virus; SQSTM1/p62: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; Ub: ubiquitin; WT: wild type