title: Major histocompatibility complex class I downregulation induced by equine herpesvirus type 1 pUL56 is through dynamin-dependent endocytosis.
abstract: Equine herpesvirus type 1 (EHV-1) downregulates cell surface expression of major histocompatibility complex class I (MHC-I) in infected cells. We have previously shown that pUL56 encoded by the EHV-1 ORF1 gene regulates the process (G. Ma, S. Feineis, N. Osterrieder, and G. R. Van de Walle, J. Virol. 86:3554-3563, 2012, doi:http://dx.doi.org/10.1128/JVI.06994-11). Here, we report that cell surface MHC-I in EHV-1-infected cells is internalized and degraded in the lysosomal compartment in a pUL56-dependent fashion. pUL56-induced MHC-I endocytosis required dynamin and tyrosine kinase but was independent of clathrin and caveolin-1, the main constituents of the clathrin- and raft/caveola-mediated endocytosis pathways, respectively. Downregulation of cell surface MHC-I was significantly inhibited by the ubiquitin-activating enzyme E1 inhibitor PYR41, indicating that ubiquitination is essential for the process. Finally, we show that downregulation is not specific for MHC-I and that other molecules, including CD46 and CD63, are also removed from the cell surface in a pUL56-dependent fashion.
  
  
  OBJECTIVE
  We show that alphaherpesvirus induces MHC-I downregulation through endocytosis, which is mediated by pUL56. The dynamin-dependent endocytic pathway is responsible for MHC-I internalization in infected cells. Furthermore, we discovered that this endocytic process can be disrupted by the inhibiting ubiquitin-activating E1 enzyme, which is indispensable for ubiquitination. Finally, pUL56 action extends to a number of cell surface molecules that are significant for host immunity. Therefore, the protein may exert a more general immunomodulatory effect.
authors.affiliation: Institut für Virologie, Freie Universität Berlin, Zentrum für Infektionsmedizin-Robert von Ostertag-Haus, Berlin, Germany.
authors.forename: Teng
authors.initials: T
authors.lastname: Huang
authors.affiliation: Department of Molecular Parasitology, Humboldt University, Berlin, Germany.
authors.forename: Maik J
authors.initials: MJ
authors.lastname: Lehmann
authors.affiliation: Institut für Virologie, Freie Universität Berlin, Zentrum für Infektionsmedizin-Robert von Ostertag-Haus, Berlin, Germany Parasitology and Animal Diseases Department, National Research Center, Dokki, Giza, Egypt.
authors.forename: Abdelrahman
authors.initials: A
authors.lastname: Said
authors.affiliation: Institut für Virologie, Freie Universität Berlin, Zentrum für Infektionsmedizin-Robert von Ostertag-Haus, Berlin, Germany.
authors.forename: Guanggang
authors.initials: G
authors.lastname: Ma
authors.affiliation: Institut für Virologie, Freie Universität Berlin, Zentrum für Infektionsmedizin-Robert von Ostertag-Haus, Berlin, Germany no.34@fu-berlin.de.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Osterrieder
mesh_terms: D000818:Animals; D002460:Cell Line; D015536:Down-Regulation; D034281:Dynamins / Q000378:metabolism*; D004705:Endocytosis; D005347:Fibroblasts / Q000276:immunology / Q000821:virology; D004861:Herpesvirus 1, Equid / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006736:Horses; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: D015395:Histocompatibility Antigens Class I; D014764:Viral Proteins; D034281:Dynamins