title: Enterovirus 71 inhibits cellular type I interferon signaling by downregulating JAK1 protein expression.
abstract: Enterovirus 71 (EV71) infection can cause severe disease and lead to death in children. Recurring outbreaks of EV71 have been reported in several countries. Interferons (IFNs) have been used for decades to treat several types of viral infection, but have a limited ability to inhibit EV71 replication. Herein, we intend to investigate the mechanisms by which EV71 inhibits the cellular type I IFN response. In this study, MRC-5 (human embryonic lung fibroblast) or RD (human rhabdomyosarcoma) cells were infected with EV71, and then treated with or without IFN-α2b. Cells were harvested and analyzed by flow cytometry to determine the level of IFNAR1. Cell lysis were prepared to detect the levels of STAT1, STAT2, phosphorylated STAT1, phosphorylated STAT2, IFNAR1, JAK1, and TYK2 by Western blotting. The phosphorylation of STAT1 and STAT2 induced by IFN were inhibited without significant downregulation of IFNAR1 in EV71-infected cells. The EV71-induced suppression of STAT1 and STAT2 phosphorylation was not rescued by the protein tyrosine phosphatases inhibitor, and was independent of suppressor of cytokine signaling protein 1/3 levels. The phosphorylation of JAK1 and TYK2 were inhibited accompanied by EV71-induced downregulation of JAK1, which occurred at a post-transcriptional level and was proteasome independent. JAK1 expression did not decrease, and IFN-α-stimulated STAT1 and STAT2 phosphorylation were not blocked in HEK293T cells overexpressing the EV71 viral protein 2A or 3C. This study demonstrates that EV71 inhibits the cellular type I IFN antiviral pathway by downregulating JAK1, while the expression of IFNAR1 does not significantly alter in EV71-infected cells. Additionally, the EV71 viral proteins 2A and 3C do not act as antagonists of cellular type I IFN signaling.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.forename: Xinghui
authors.initials: X
authors.lastname: Zhao
authors.forename: Rui
authors.initials: R
authors.lastname: Yu
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Zhang
authors.forename: Shipo
authors.initials: S
authors.lastname: Wu
authors.forename: Ju
authors.initials: J
authors.lastname: Liu
authors.forename: Xiangyang
authors.initials: X
authors.lastname: Chi
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Song
authors.forename: Ling
authors.initials: L
authors.lastname: Fu
authors.forename: Yingqun
authors.initials: Y
authors.lastname: Yu
authors.forename: Lihua
authors.initials: L
authors.lastname: Hou
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
mesh_terms: D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D015536:Down-Regulation; D029821:Enterovirus A, Human / Q000502:physiology*; D005347:Fibroblasts; D006801:Humans; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism*; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D021122:Protein Subunits; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism; D012208:Rhabdomyosarcoma; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014709:Vero Cells
chemical_list: C507964:IFNAR1 protein, human; D007370:Interferon Type I; D021122:Protein Subunits; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D053633:Receptor, Interferon alpha-beta; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D017027:Protein Tyrosine Phosphatases