title: The extracellular interactome of the human adenovirus family reveals diverse strategies for immunomodulation.
abstract: Viruses encode secreted and cell-surface expressed proteins essential to modulate host immune defenses and establish productive infections. However, to date there has been no systematic study of the extracellular interactome of any human virus. Here we utilize the E3 proteins, diverse and rapidly evolving transmembrane-containing proteins encoded by human adenoviruses, as a model system to survey the extracellular immunomodulatory landscape. From a large-scale protein interaction screen against a microarray of more than 1,500 human proteins, we find and validate 51 previously unidentified virus-host interactions. Our results uncover conserved strategies as well as substantial diversity and multifunctionality in host targeting within and between viral species. Prominent modulation of the leukocyte immunoglobulin-like and signalling lymphocyte activation molecule families and a number of inhibitory receptors were identified as hubs for viral perturbation, suggesting unrecognized immunoregulatory strategies. We describe a virus-host extracellular interaction map of unprecedented scale that provides new insights into viral immunomodulation.
authors.affiliation: Department of Protein Chemistry, Genentech, 470 East Grand Avenue, South San Francisco, California 94080, USA.
authors.forename: Nadia
authors.initials: N
authors.lastname: Martinez-Martin
authors.affiliation: Department of Protein Chemistry, Genentech, 470 East Grand Avenue, South San Francisco, California 94080, USA.
authors.forename: Sree R
authors.initials: SR
authors.lastname: Ramani
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech, 455 East Grand Avenue, South San Francisco, California 94080, USA.
authors.forename: Jason A
authors.identifier: http://orcid.org/0000-0002-5922-563X
authors.initials: JA
authors.lastname: Hackney
authors.affiliation: Department of Protein Chemistry, Genentech, 470 East Grand Avenue, South San Francisco, California 94080, USA.
authors.forename: Irene
authors.initials: I
authors.lastname: Tom
authors.affiliation: Department of Protein Chemistry, Genentech, 470 East Grand Avenue, South San Francisco, California 94080, USA.
authors.forename: Bernd J
authors.initials: BJ
authors.lastname: Wranik
authors.affiliation: Department of Protein Chemistry, Genentech, 470 East Grand Avenue, South San Francisco, California 94080, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Chan
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech, 455 East Grand Avenue, South San Francisco, California 94080, USA.
authors.forename: Johnny
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Protein Chemistry, Genentech, 470 East Grand Avenue, South San Francisco, California 94080, USA.
authors.forename: Maciej T
authors.initials: MT
authors.lastname: Paluch
authors.affiliation: Department of Protein Chemistry, Genentech, 470 East Grand Avenue, South San Francisco, California 94080, USA.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Department of Protein Chemistry, Genentech, 470 East Grand Avenue, South San Francisco, California 94080, USA.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Hass
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech, 455 East Grand Avenue, South San Francisco, California 94080, USA.
authors.forename: Hilary
authors.initials: H
authors.lastname: Clark
authors.affiliation: Department of Protein Chemistry, Genentech, 470 East Grand Avenue, South San Francisco, California 94080, USA.
authors.forename: Lino C
authors.initials: LC
authors.lastname: Gonzalez
mesh_terms: D000072283:A549 Cells; D000260:Adenoviruses, Human / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003412:Cricetulus; D005110:Extracellular Space / Q000276:immunology / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D056747:Immunomodulation / Q000276:immunology*; D019169:Jurkat Cells; D020014:K562 Cells; D011485:Protein Binding; D060066:Protein Interaction Maps / Q000276:immunology*; D020543:Proteome / Q000276:immunology / Q000378:metabolism; D014764:Viral Proteins / Q000276:immunology* / Q000378:metabolism
chemical_list: D020543:Proteome; D014764:Viral Proteins