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- Title
PIAS1-mediated SUMOylation of influenza A virus PB2 restricts viral replication and virulence.
- Authors
Wang, Guangwen; Zhao, Yuhui; Zhou, Yuan; Jiang, Li; Liang, Libin; Kong, Fandi; Yan, Ya; Wang, Xuyuan; Wang, Yihan; Wen, Xia; Zeng, Xianying; Tian, Guobin; Deng, Guohua; Shi, Jianzhong; Liu, Liling; Chen, Hualan; Li, Chengjun
- Abstract
Host defense systems employ posttranslational modifications to protect against invading pathogens. Here, we found that protein inhibitor of activated STAT 1 (PIAS1) interacts with the nucleoprotein (NP), polymerase basic protein 1 (PB1), and polymerase basic protein 2 (PB2) of influenza A virus (IAV). Lentiviral-mediated stable overexpression of PIAS1 dramatically suppressed the replication of IAV, whereas siRNA knockdown or CRISPR/Cas9 knockout of PIAS1 expression significantly increased virus growth. The expression of PIAS1 was significantly induced upon IAV infection in both cell culture and mice, and PIAS1 was involved in the overall increase in cellular SUMOylation induced by IAV infection. We found that PIAS1 inhibited the activity of the viral RNP complex, whereas the C351S or W372A mutant of PIAS1, which lacks the SUMO E3 ligase activity, lost the ability to suppress the activity of the viral RNP complex. Notably, the SUMO E3 ligase activity of PIAS1 catalyzed robust SUMOylation of PB2, but had no role in PB1 SUMOylation and a minimal role in NP SUMOylation. Moreover, PIAS1-mediated SUMOylation remarkably reduced the stability of IAV PB2. When tested in vivo, we found that the downregulation of PIAS1 expression in mice enhanced the growth and virulence of IAV. Together, our findings define PIAS1 as a restriction factor for the replication and pathogenesis of IAV. Author summary: SUMOylation appears to be an important posttranslational modification mechanism of proteins, including viral proteins. In the present study, we found that the SUMO E3 ligase PIAS1 interacts with the PB2, PB1, and NP proteins of the RNP complex of IAV. PIAS1 expression was found to suppress the viral RNP complex activity. Mechanistically, the SUMO E3 ligase activity of PIAS1 led to robust SUMOylation of IAV PB2, but had no or a minimal effect on the SUMOylation of PB1 and NP, respectively, and PIAS1-mediated SUMOylation significantly decreased the stability of PB2. The expression of PIAS1 was markedly induced upon IAV infection in cell culture and mice, indicating that PIAS1 is actively involved and biologically important in the inhibition of IAV replication. Of note, the role of PIAS1 in restricting the replication and virulence of IAV was directly verified in Pias1+/- mice. Our findings thus identify a SUMO E3 ligase that interacts with and SUMOylates IAV PB2, thereby leading to reduced virus replication and virulence in vitro and in vivo.
- Subjects
INFLUENZA A virus; BASIC proteins; UBIQUITIN ligases; VIRAL replication; INFLUENZA viruses
- Publication
PLoS Pathogens, 2022, Vol 18, Issue 4, p1
- ISSN
1553-7366
- Publication type
Article
- DOI
10.1371/journal.ppat.1010446