title: Vaccinia virus entry is followed by core activation and proteasome-mediated release of the immunomodulatory effector VH1 from lateral bodies.
abstract: Host cell entry of vaccinia virus, the prototypic poxvirus, involves a membrane fusion event delivering the viral core and two proteinaceous lateral bodies (LBs) into the cytosol. Uncoating of viral cores is poorly characterized, and the composition and function of LBs remains enigmatic. We found that cytosolic cores rapidly dissociated from LBs and expanded in volume, which coincided with reduction of disulfide-bonded core proteins. We identified the abundant phosphoprotein F17, the dual-specificity phosphatase VH1, and the oxidoreductase G4 as bona fide LB components. After reaching the cytosol, F17 was degraded in a proteasome-dependent manner. Proteasome activity, and presumably LB disassembly, was required for the immediate immunomodulatory activity of VH1: dephosphorylation of STAT1 to prevent interferon-γ-mediated antiviral responses. These results reveal a mechanism used by poxviruses to deliver viral enzymes to the host cell cytosol and are likely to facilitate the identification of additional LB-resident viral effectors.
authors.affiliation: Institute of Biochemistry, ETH Zurich, 8093 Zurich, Switzerland.
authors.forename: Florian Ingo
authors.initials: FI
authors.lastname: Schmidt
authors.forename: Christopher Karl Ernst
authors.initials: CK
authors.lastname: Bleck
authors.forename: Lucia
authors.initials: L
authors.lastname: Reh
authors.forename: Karel
authors.initials: K
authors.lastname: Novy
authors.forename: Bernd
authors.initials: B
authors.lastname: Wollscheid
authors.forename: Ari
authors.initials: A
authors.lastname: Helenius
authors.forename: Henning
authors.initials: H
authors.lastname: Stahlberg
authors.forename: Jason
authors.initials: J
authors.lastname: Mercer
mesh_terms: D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D054637:Dual-Specificity Phosphatases / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014615:Vaccinia / Q000201:enzymology / Q000378:metabolism* / Q000821:virology*; D014616:Vaccinia virus / Q000201:enzymology / Q000378:metabolism / Q000502:physiology*; D014764:Viral Proteins / Q000378:metabolism*; D014775:Virus Activation
chemical_list: D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D014764:Viral Proteins; C489855:dual specificity phosphatase 12; D054637:Dual-Specificity Phosphatases; D046988:Proteasome Endopeptidase Complex