title: HSV-2 immediate-early protein US1 inhibits IFN-β production by suppressing association of IRF-3 with IFN-β promoter.
abstract: HSV-2 is the major cause of genital herpes, and its infection increases the risk of HIV-1 acquisition and transmission. After initial infection, HSV-2 can establish latency within the nervous system and thus maintains lifelong infection in humans. It has been suggested that HSV-2 can inhibit type I IFN signaling, but the underlying mechanism has yet to be determined. In this study, we demonstrate that productive HSV-2 infection suppresses Sendai virus (SeV) or polyinosinic-polycytidylic acid-induced IFN-β production. We further reveal that US1, an immediate-early protein of HSV-2, contributes to such suppression, showing that US1 inhibits IFN-β promoter activity and IFN-β production at both mRNA and protein levels, whereas US1 knockout significantly impairs such capability in the context of HSV-2 infection. US1 directly interacts with DNA binding domain of IRF-3, and such interaction suppresses the association of nuclear IRF-3 with the IRF-3 responsive domain of IFN-β promoter, resulting in the suppression of IFN-β promoter activation. Additional studies demonstrate that the 217-414 aa domain of US1 is critical for the suppression of IFN-β production. Our results indicate that HSV-2 US1 downmodulates IFN-β production by suppressing the association of IRF-3 with the IRF-3 responsive domain of IFN-β promoter. Our findings highlight the significance of HSV-2 US1 in inhibiting IFN-β production and provide insights into the molecular mechanism by which HSV-2 evades the host innate immunity, representing an unconventional strategy exploited by a dsDNA virus to interrupt type I IFN signaling pathway.
authors.affiliation: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; University of Chinese Academy of Sciences, Beijing 100049, China; and.
authors.forename: Mudan
authors.initials: M
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China;
authors.forename: Yalan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; University of Chinese Academy of Sciences, Beijing 100049, China; and.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; University of Chinese Academy of Sciences, Beijing 100049, China; and.
authors.forename: Xinmeng
authors.initials: X
authors.lastname: Guan
authors.affiliation: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; University of Chinese Academy of Sciences, Beijing 100049, China; and.
authors.forename: Siyi
authors.initials: S
authors.lastname: He
authors.affiliation: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; University of Chinese Academy of Sciences, Beijing 100049, China; and.
authors.forename: Sukun
authors.initials: S
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; University of Chinese Academy of Sciences, Beijing 100049, China; and.
authors.forename: Chang
authors.initials: C
authors.lastname: Li
authors.affiliation: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China;
authors.forename: Kai
authors.initials: K
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; University of Chinese Academy of Sciences, Beijing 100049, China; and.
authors.forename: Wei
authors.initials: W
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China;
authors.forename: Tao
authors.initials: T
authors.lastname: Du
authors.affiliation: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; University of Chinese Academy of Sciences, Beijing 100049, China; and.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yan
authors.affiliation: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China;
authors.forename: Zhenfeng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China;
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China;
authors.forename: Hanzhong
authors.initials: H
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; Institute for Infection and Immunity, St George's University of London, London SW17 0RE, United Kingdom qhu@wh.iov.cn.
authors.forename: Qinxue
authors.initials: Q
authors.lastname: Hu
mesh_terms: D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation; D018258:Herpesvirus 2, Human / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D050838:Interferon Regulatory Factor-3 / Q000737:chemistry / Q000378:metabolism*; D016899:Interferon-beta / Q000096:biosynthesis* / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D015398:Signal Transduction
chemical_list: D017874:Immediate-Early Proteins; D050838:Interferon Regulatory Factor-3; C527356:US1 protein, human herpesvirus 2; D016899:Interferon-beta