Open AccessPIAS1-mediated SUMOylation of influenza A virus PB2 restricts viral replication and virulence
Author(s) -
Guangwen Wang,
Yuhui Zhao,
Yuan Zhou,
Jiang Li,
Liang Liu,
Kong Fandi,
Yan Ya,
Xuyuan Wang,
Yihan Wang,
Xin Wen,
Xianying Zeng,
Guobin Tian,
Guohua Deng,
Jianzhong Shi,
Liling Liu,
Hualan Chen,
Chengjun Li
Publication year - 2022
Publication title -
plos pathogens
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.719
H-Index - 206
eISSN - 1553-7374
pISSN - 1553-7366
DOI - 10.1371/journal.ppat.1010446
Subject(s) - sumo protein , influenza a virus , hek 293 cells , ubiquitin ligase , gene knockdown , biology , viral replication , virology , microbiology and biotechnology , virus , chemistry , ubiquitin , cell culture , gene , genetics
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.