State Key Laboratory of Oncology in South China, MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, GD, China.
Institute of Human Virology, Zhongshan School of Medicine, and Key Laboratory of Tropical Diseases Control Ministry of Education, Sun Yat-sen University, Guangzhou, GD, China.
Autophagy. 2021 Jun;17(6):1379-1392. doi: 10.1080/15548627.2020.1761653. Epub 2020 May 31.
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. ATG5: autophagy related gene 5; Baf A: bafilomycin A; 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.
IRF3（干扰素调节因子 3）是抗病毒先天免疫信号转导中最重要的转录因子之一，在多种细胞中广泛表达。虽然已经证明 IRF3 在病毒感染过程中可以引发多种细胞过程，包括 I 型干扰素（IFN）的产生，但 IRF3 活性的精确调节机制仍不完全清楚。在这里，我们报告说，货物受体 CALCOCO2/NDP52 介导的选择性巨自噬/自噬以病毒载量依赖的方式促进 IRF3 的降解。去泛素酶 PSMD14/POH1 通过在 IRF3 的赖氨酸 313 上切割 K27 连接的多泛素链，防止 IRF3 发生自噬降解，从而维持其基础水平和 IRF3 介导的 I 型 IFN 激活。PSMD14 或 CALCOCO2 介导的 IRF3 自噬降解确保了 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 IFN 激活与免疫抑制方面的调节作用，并为选择性自噬和 I 型 IFN 信号转导之间的串扰提供了新的见解。ATG5：自噬相关基因 5；Baf A：巴弗霉素 A；BECN1：beclin 1；CALCOCO2/NDP52：钙结合和卷曲螺旋结构域 2；CGAS：环鸟苷酸-AMP 合酶；DDX58/RIG-I：DExD/H 盒螺旋酶 58；DUBs：去泛素化酶；IFN：干扰素；IRF3：干扰素调节因子 3；MAVS：线粒体抗病毒信号蛋白；MOI：感染复数；PAMPs：病原体相关分子模式；PBMC：外周血单核细胞；PSMD14/POH1：蛋白酶体 26S 亚基，非 ATP 酶 14；RIPA：RLR 诱导的 IRF3 介导的细胞凋亡途径；SeV：仙台病毒；SQSTM1/p62：自噬相关蛋白 1；STING1：干扰素反应 cGAMP 相互作用蛋白 1 的刺激物；TBK1：TANK 结合激酶 1；Ub：泛素；WT：野生型。
