JEM . . . The bell wave group reveals the mechanism by which the ubiquity asse USP22 regulates the natural immune response of the antiviral.

Interferon type I is an important cytokine to protect the body against viral infection. Its expression is an important marker event in the early stage of viral infection. It is regulated by transcription factors IRF3 and NF - κ B.the activation of IRF3 is strictly regulated at multiple levels, including ubiquitination, phosphorylation, dimerization and nuclear translocation.at present, the phosphorylation, ubiquitination and dimerization of IRF3 have been well studied, but the mechanism of IRF3 nuclear translocation is less studied.early research results showed that kpna3 / 4 of importin α family, which was obtained from bacteria or baculovirus, interacted with IRF3. However, the later studies showed that knockdown of kpna3 / 4 did not affect the expression of downstream genes such as interferon type I after virus infection, suggesting that there are other importin α family proteins involved in IRF3 nuclear translocation.on March 4, 2020, Professor Zhong Bo, School of medical research / School of life sciences, Wuhan University, published an online issue entitled USP22 promoters IRF3 nuclear translocation and anti viral responses by debiquishing the import protein kpna2 They found that the ubiquitinase USP22 regulates the natural immune response to antiviral agents by de ubiquitination and stabilizing the nuclear transporter kpna2, thereby promoting the nuclear translocation of IRF3 after viral infection.the research group first screened the de ubiquitinase that interacted with IRF3 through immunoprecipitation test, and found that USP22 interacted with IRF3.USP22 was localized in both cytoplasm and nucleus. USP22 in nucleus was involved in histone de ubiquitination, DNA damage repair, cell cycle and antibody class transition.however, the function of USP22 in the cytoplasm and the biological process of its regulation are still unclear.they first found that the interaction between USP22 and IRF3 depended on the induction of viral infection, and this process occurred in the cytoplasm rather than the nucleus.knockdown or knockout of USP22 inhibits the expression of downstream genes such as interferon type I induced by viral infection, and promotes virus replication. This process depends on the activity of its de ubiquitinase rather than the localization of USP22 in the nucleus, suggesting that USP22 mainly plays a role in the cytoplasm.further studies showed that USP22 knockout did not affect the ubiquitination level, stability, phosphorylation and dimerization of IRF3 before and after virus infection, but inhibited the transport of IRF3 from cytoplasm to nucleus after virus infection, indicating that USP22 regulates IRF3 nuclear entry induced by virus infection, which is not realized by direct de ubiquitination of IRF3.considering that the nuclear transport of proteins depends on the importin α family proteins, they further screened importin α which interacted with IRF3 and USP22, and found that kpna2 had both effects.in USP22 knockout cells, the ubiquitination of kpna2 was enhanced and the degradation rate was accelerated, which depended on NDP52 mediated selective autophagy.knockdown of kpna2 can significantly inhibit the nuclear translocation of IRF3 induced by virus infection and the expression of downstream genes such as interferon type I. The expression of kpna2 in USP22 knockout cells can save the nuclear translocation of IRF3 induced by virus infection and inhibit virus replication.these results elucidate the new function of cytoplasmic USP22 and the new regulatory mechanism of IRF3 nuclear translocation induced by viral infection.it is reported that CAI, a 2016 doctoral student in the school of life sciences, Wuhan University, was the first author of the paper, and Professor Zhong Bo from the school of life sciences / Medical Research Institute and the center for frontier science of immunology and metabolism was the corresponding author.original link: plate maker: Ke