title: Human bocavirus VP2 upregulates IFN-β pathway by inhibiting ring finger protein 125-mediated ubiquitination of retinoic acid-inducible gene-I.
abstract: Precise regulation of innate immunity is crucial for maintaining optimal immune responses against infections. Whereas positive regulation of IFN signaling elicits rapid type I IFNs, negative regulation is equally important in preventing the production of superfluous IFNs that can be hazardous to the host. The positive regulators of IFN pathway are known to be the main targets of viruses to antagonize the innate immune system. Whether viruses target the negative regulators of IFN pathway remains to be fully investigated. In this study, we report that the structural protein VP2 of human Bocavirus modulates IFN pathway by targeting the ring finger protein 125 (RNF125), a negative regulator of type I IFN signaling, which conjugates Lys(48)-linked ubiquitination to retinoic acid-inducible gene-I (RIG-I) and subsequently leads to the proteasome-dependent degradation of RIG-I. VP2 not only upregulated Sendai virus (SeV)-induced IFNB promoter activity, but also enhanced SeV-induced IFN-β production at both mRNA and protein levels. In agreement, the level of Ser(396)-phosphorylated IFN regulatory factor 3 stimulated by SeV was enhanced in the presence of VP2. Furthermore, VP2 was demonstrated to physically interact with RNF125, resulting in the reduction of RNF125-mediated ubiquitination and proteasome-dependent degradation of RIG-I. Additional study indicated that endogenous RIG-I degradation was decreased in VP2-expressing cells. Our study delineates a unique phenomenon for aberrant activation of IFN regulatory factor 3 pathway and may represent a new mechanism underlying viral manipulation of the host immune system.
authors.affiliation: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.
authors.forename: Huanle
authors.initials: H
authors.lastname: Luo
authors.forename: Zhenfeng
authors.initials: Z
authors.lastname: Zhang
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Zheng
authors.forename: Xianliang
authors.initials: X
authors.lastname: Ke
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zhang
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Bingke
authors.initials: B
authors.lastname: Bai
authors.forename: Panyong
authors.initials: P
authors.lastname: Mao
authors.forename: Qinxue
authors.initials: Q
authors.lastname: Hu
authors.forename: Hanzhong
authors.initials: H
authors.lastname: Wang
mesh_terms: D036022:Capsid Proteins / Q000378:metabolism*; D002460:Cell Line; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D056661:Human bocavirus; D006801:Humans; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic; D029082:Sendai virus; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D036022:Capsid Proteins; D050838:Interferon Regulatory Factor-3; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D016899:Interferon-beta; C551868:RNF125 protein, human; D044767:Ubiquitin-Protein Ligases; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases