Nef-induced CD4 degradation: a diacidic-based motif in Nef functions as a lysosomal targeting signal through the binding of beta-COP in endosomes.
The Nef protein of primate lentiviruses downregulates the cell surface expression of CD4 through a two-step process. First, Nef connects the cytoplasmic tail of CD4 with adaptor protein complexes (AP), thereby inducing the formation of CD4-specific clathrin-coated pits that rapidly endocytose the viral receptor. Second, Nef targets internalized CD4 molecules for degradation. Here we show that Nef accomplishes this second task by acting as a connector between CD4 and the beta subunit of COPI coatomers in endosomes. A sequence encompassing a critical acidic dipeptide, located nearby but distinct from the AP-binding determinant of HIV-1 Nef, is responsible for beta-COP recruitment and for routing to lysosomes. A novel class of endosomal sorting motif, based on acidic residues, is thus revealed, and beta-COP is identified as its downstream partner.
Piguet
V
V
Department of Genetics, Faculty of Medicine, University of Geneva, Switzerland.
Gu
F
F
Foti
M
M
Demaurex
N
N
Gruenberg
J
J
Carpentier
J L
JL
Trono
D
D
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D015704:CD4 Antigens / Q000378:metabolism*; D016466:CHO Cells; D002460:Cell Line; D020756:Coatomer Protein; D006224:Cricetinae; D004151:Dipeptides / Q000502:physiology; D015536:Down-Regulation / Q000502:physiology; D011992:Endosomes / Q000378:metabolism* / Q000502:physiology; D015693:Gene Products, nef / Q000502:physiology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007668:Kidney; D008247:Lysosomes / Q000378:metabolism / Q000502:physiology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism* / Q000502:physiology; D008969:Molecular Sequence Data; D015398:Signal Transduction / Q000502:physiology*; D054311:nef Gene Products, Human Immunodeficiency Virus
D015704:CD4 Antigens; D020756:Coatomer Protein; D004151:Dipeptides; D015693:Gene Products, nef; D008869:Microtubule-Associated Proteins; D054311:nef Gene Products, Human Immunodeficiency Virus