title: Mouse mammary tumor virus uses mouse but not human transferrin receptor 1 to reach a low pH compartment and infect cells.
abstract: Mouse mammary tumor virus (MMTV) is a pH-dependent virus that uses mouse transferrin receptor 1 (TfR1) for entry into cells. Previous studies demonstrated that MMTV could induce pH 5-dependent fusion-from-with of mouse cells. Here we show that the MMTV envelope-mediated cell-cell fusion requires both the entry receptor and low pH (pH 5). Although expression of the MMTV envelope and TfR1 was sufficient to mediate low pH-dependent syncytia formation, virus infection required trafficking to a low pH compartment; infection was independent of cathepsin-mediated proteolysis. Human TfR1 did not support virus infection, although envelope-mediated syncytia formation occurred with human cells after pH 5 treatment and this fusion depended on TfR1 expression. However, although the MMTV envelope bound human TfR1, virus was only internalized and trafficked to a low pH compartment in cells expressing mouse TfR1. Thus, while human TfR1 supported cell-cell fusion, because it was not internalized when bound to MMTV, it did not function as an entry receptor. Our data suggest that MMTV uses TfR1 for all steps of entry: cell attachment, induction of the conformational changes in Env required for membrane fusion and internalization to an appropriate acidic compartment.
authors.affiliation: Department of Microbiology and Abramson Family Cancer Center, University of Pennsylvania, 313BRBII/III, 421 Curie Blvd., Philadelphia, PA 19104, USA.
authors.forename: Enxiu
authors.initials: E
authors.lastname: Wang
authors.forename: Nyamekye
authors.initials: N
authors.lastname: Obeng-Adjei
authors.forename: Qihua
authors.initials: Q
authors.lastname: Ying
authors.forename: Laurent
authors.initials: L
authors.lastname: Meertens
authors.forename: Tanya
authors.initials: T
authors.lastname: Dragic
authors.forename: Robert A
authors.initials: RA
authors.lastname: Davey
authors.forename: Susan R
authors.initials: SR
authors.lastname: Ross
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002451:Cell Compartmentation; D002460:Cell Line; D011992:Endosomes / Q000821:virology; D005786:Gene Expression Regulation; D015686:Gene Products, env / Q000378:metabolism; D015726:Giant Cells / Q000821:virology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D010447:Peptide Hydrolases / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D011990:Receptors, Transferrin / Q000378:metabolism*; D053586:Virus Internalization
chemical_list: D015703:Antigens, CD; C068126:CD71 antigen; D015686:Gene Products, env; D011990:Receptors, Transferrin; C480029:Tfrc protein, mouse; D010447:Peptide Hydrolases