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

The Journal of Experimental Medicine
Zeng CaiBo Zhong

Abstract

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 KPNA2 after viral infection. Viral infection induced USP22-IRF3 association in the cytoplasm in a KPNA2-depedent manner, and knockdown or knockout of USP22 or KPNA2 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 KPNA2 after viral infection to facilitate efficient nuclear translocation of IRF3. Reconstitution of KPNA2 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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Citations

Sep 28, 2020·Cell Reports·Hongjie XiaPei-Yong Shi
Feb 19, 2021·Molecular Therapy : the Journal of the American Society of Gene Therapy·Min LiXuanming Yang
Feb 21, 2021·Cytokine & Growth Factor Reviews·Jorge Quarleri, M Victoria Delpino
May 15, 2021·Cancer Letters·Tingting FengXiao Xu
May 18, 2021·Frontiers in Immunology·Raphaël JamiStéphane Biacchesi

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Methods Mentioned

BETA
nuclear translocation
deubiquitination
Immunoprecipitation
reverse transcription PCR
Genotyping
Flow cytometry
ELISA
ubiquitination
pull-down
transfection

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