title: Expression of human immunodeficiency virus type 1 gag modulates ligand-induced downregulation of EGF receptor.
abstract: Many enveloped viruses use the ESCRT proteins of the cellular vacuolar protein sorting pathway for efficient egress from the cell. Recruitment of the ESCRT proteins by human immunodeficiency virus type 1 (HIV-1) Gag is required for HIV-1 particle budding and egress. ESCRT proteins normally function at endosomal membranes, where they facilitate the downregulation of mitogen-activated receptors such as EGF receptor (EGFR) through multivesicular body biogenesis. It is not known whether the Gag-mediated recruitment of ESCRT proteins functionally depletes the pool of these molecules that is available for the downregulation of EGFR. Here we show that the expression of HIV-1 Gag decreases the rate of EGFR downregulation, as assessed by decreases in the rates of (125)I-EGF and EGFR degradation. The effect of Gag was dependent on the presence of the TSG101 binding motif (PTAP) within the Gag C-terminal p6 domain. Cells expressing HIV-1 Gag retained more EGFR in late endosomes. This effect occurred when Gag was expressed alone from a heterologous promoter and when Gag expression was driven by the HIV-1 long terminal repeat within pHXB2DeltaBalD25S, a noninfectious lentiviral vector. Gag-expressing cells exhibited higher levels of activated mitogen-activated protein kinase for longer times after EGF addition than did cells that did not express HIV-1 Gag. These results indicate that HIV-1 Gag can impinge upon the functioning of the cellular vacuolar protein sorting pathway and reveal yet another facet of the intricate effects of HIV-1 infection on host cell physiology.
authors.affiliation: Cell Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 143, New York, NY 10021, USA.
authors.forename: Rajeshwari R
authors.initials: RR
authors.lastname: Valiathan
authors.forename: Marilyn D
authors.initials: MD
authors.lastname: Resh
mesh_terms: D000818:Animals; D019556:COS Cells; D015536:Down-Regulation; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D015683:Gene Products, gag / Q000502:physiology*; D015497:HIV-1 / Q000502:physiology*; D008024:Ligands; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D021381:Protein Transport; D014162:Transfection
chemical_list: D015683:Gene Products, gag; D008024:Ligands; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases