title: ITCH E3 Ubiquitin Ligase Interacts with Ebola Virus VP40 To Regulate Budding.
abstract: Ebola virus (EBOV) and Marburg virus (MARV) belong to the Filoviridae family and can cause outbreaks of severe hemorrhagic fever, with high mortality rates in humans. The EBOV VP40 (eVP40) and MARV VP40 (mVP40) matrix proteins play a central role in virion assembly and egress, such that independent expression of VP40 leads to the production and egress of virus-like particles (VLPs) that accurately mimic the budding of infectious virus. Late (L) budding domains of eVP40 recruit host proteins (e.g., Tsg101, Nedd4, and Alix) that are important for efficient virus egress and spread. For example, the PPxY-type L domain of eVP40 and mVP40 recruits the host Nedd4 E3 ubiquitin ligase via its WW domains to facilitate budding. Here we sought to identify additional WW domain host interactors and demonstrate that the PPxY L domain motif of eVP40 interacts specifically with the WW domain of the host E3 ubiquitin ligase ITCH. ITCH, like Nedd4, is a member of the HECT class of E3 ubiquitin ligases, and the resultant physical and functional interaction with eVP40 facilitates VLP and virus budding. Identification of this novel eVP40 interactor highlights the functional interplay between cellular E3 ligases, ubiquitination, and regulation of VP40-mediated egress.
  
  
  
  The unprecedented magnitude and scope of the recent 2014-2015 EBOV outbreak in West Africa and its emergence here in the United States and other countries underscore the critical need for a better understanding of the biology and pathogenesis of this emerging pathogen. We have identified a novel and functional EBOV VP40 interactor, ITCH, that regulates VP40-mediated egress. This virus-host interaction may represent a new target for our previously identified small-molecule inhibitors of virus egress.
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Ziying
authors.initials: Z
authors.lastname: Han
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, M. D. Anderson Cancer Center, University of Texas, Smithville, Texas, USA.
authors.forename: Cari A
authors.initials: CA
authors.lastname: Sagum
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, M. D. Anderson Cancer Center, University of Texas, Smithville, Texas, USA.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Bedford
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Sachdev S
authors.initials: SS
authors.lastname: Sidhu
authors.affiliation: Department of Physiology, Institute for Molecular and Cell Biology (IMCB, AStar), National University of Singapore, Singapore.
authors.forename: Marius
authors.initials: M
authors.lastname: Sudol
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA rharty@vet.upenn.edu.
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Harty
mesh_terms: D000818:Animals; D002460:Cell Line; D029043:Ebolavirus / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D009698:Nucleoproteins / Q000378:metabolism*; D025941:Protein Interaction Mapping; D012097:Repressor Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D014758:Viral Core Proteins / Q000378:metabolism*; D057074:Virus Release
chemical_list: D009698:Nucleoproteins; D012097:Repressor Proteins; D014758:Viral Core Proteins; C084819:nucleoprotein VP40, Ebola virus; C432966:ITCH protein, human; D044767:Ubiquitin-Protein Ligases