USP22 promotes IRF3 nuclear translocation and antiviral responses by deubiquitinating the importin protein KPNA2.

USP22 is a cytoplasmic and nuclear deubiquitinating enzyme, and the functions of cytoplasmic USP22 are unclear. Here, we discovered that cytoplasmic USP22 promoted nuclear translocation of IRF3 by deubiquitianting and stabilizing after viral infection. Viral infection induced USP22-IRF3 association in the cytoplasm in a manner, and knockdown or knockout of USP22 or Kduanyu15352 impaired IRF3 nuclear translocation and expression of downstream genes after viral infection. Consistently, Cre-ER Usp22fl/fl or Lyz2-Cre Usp22fl/fl mice produced decreased levels of type I IFNs after viral infection and exhibited increased susceptibility to lethal viral infection compared with the respective control littermates. Mechanistically, USP22 deubiquitinated and stabilized Kduanyu15352 after viral infection to facilitate efficient nuclear translocation of IRF3. Reconstitution of Kduanyu15352 into USP22 knockout cells restored virus-triggered nuclear translocation of IRF3 and cellular antiviral responses. These findings define a previously unknown function of cytoplasmic USP22 and establish a mechanistic link between USP22 and IRF3 nuclear translocation that expands potential therapeutic strategies for infectious diseases.

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