Selective autophagy controls the stability of transcription factor IRF3 to balance type I interferon production and immune suppression

Autophagy. 2021 Jun;17(6):1379-1392. doi: 10.1080/15548627.2020.1761653. Epub 2020 May 31.

Abstract

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.

Keywords: Antiviral immunity; deubiquitination; immune suppression; selective autophagy; type I interferon signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagy / immunology*
  • Humans
  • Immunity, Innate / immunology
  • Interferon Regulatory Factor-3 / immunology
  • Interferon Regulatory Factor-3 / metabolism*
  • Interferon Type I / immunology
  • Interferon Type I / metabolism*
  • Leukocytes, Mononuclear / immunology
  • Leukocytes, Mononuclear / metabolism*
  • Macroautophagy / immunology
  • Trans-Activators / metabolism
  • Virus Diseases / immunology

Substances

  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Interferon Type I
  • Trans-Activators

Grants and funding

This work was supported by National Natural Science Foundation of China [31870862, 31700760, 31970700, and 31800751], Science and Technology Planning Project of Guangzhou, China [201804010385], National Key Basic Research Program of China [2015CB554301], and the Fundamental Research Funds for the Central Universities [18lgpy49 and 18lgpy53].