title: The soluble serum protein Gas6 bridges virion envelope phosphatidylserine to the TAM receptor tyrosine kinase Axl to mediate viral entry.
abstract: Virus entry into cells is typically initiated by binding of virally encoded envelope proteins to specific cell surface receptors. Studying infectivity of lentivirus pseudotypes lacking envelope binding, we still observed high infectivity for some cell types. On further investigation, we discovered that this infectivity is conferred by the soluble bovine protein S in fetal calf serum, or Gas6, its human homolog. Gas6 enhances native infectivity of pseudotypes of multiple viral envelope proteins. Gas6 mediates binding of the virus to target cells by bridging virion envelope phosphatidylserine to Axl, a TAM receptor tyrosine kinase on target cells. Phagocytic clearance of apoptotic cells is known to involve bridging by Gas6. Replication of vaccinia virus, which was previously reported to use apoptotic mimicry to enter cells, is also enhanced by Gas6. These results reveal an alternative molecular mechanism of viral entry that can broaden host range and enhance infectivity of enveloped viruses.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Kouki
authors.initials: K
authors.lastname: Morizono
authors.forename: Yiming
authors.initials: Y
authors.lastname: Xie
authors.forename: Tove
authors.initials: T
authors.lastname: Olafsen
authors.forename: Benhur
authors.initials: B
authors.lastname: Lee
authors.forename: Asim
authors.initials: A
authors.lastname: Dasgupta
authors.forename: Anna M
authors.initials: AM
authors.lastname: Wu
authors.forename: Irvin S Y
authors.initials: IS
authors.lastname: Chen
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D006224:Cricetinae; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D010587:Phagocytosis / Q000502:physiology; D010718:Phosphatidylserines / Q000378:metabolism*; D017293:Protein S / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D011956:Receptors, Cell Surface; D017386:Sequence Homology, Amino Acid; D014616:Vaccinia virus / Q000502:physiology; D014759:Viral Envelope Proteins / Q000378:metabolism*; D053585:Virus Attachment; D053586:Virus Internalization; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D010718:Phosphatidylserines; D017293:Protein S; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D011956:Receptors, Cell Surface; D014759:Viral Envelope Proteins; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6