Nef-induced CD4 degradation: a diacidic-based motif in Nef functions as a lysosomal targeting signal through the binding of beta-COP in endosomes

Cell. 1999 Apr 2;97(1):63-73. doi: 10.1016/s0092-8674(00)80715-1.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites / physiology
  • CD4 Antigens / metabolism*
  • CHO Cells
  • Cell Line
  • Coatomer Protein
  • Cricetinae
  • Dipeptides / physiology
  • Down-Regulation / physiology
  • Endosomes / metabolism*
  • Endosomes / physiology
  • Gene Products, nef / physiology*
  • HIV-1 / physiology*
  • Humans
  • Hydrogen-Ion Concentration
  • Kidney
  • Lysosomes / metabolism
  • Lysosomes / physiology*
  • Microtubule-Associated Proteins / metabolism*
  • Microtubule-Associated Proteins / physiology
  • Molecular Sequence Data
  • Signal Transduction / physiology*
  • nef Gene Products, Human Immunodeficiency Virus


  • CD4 Antigens
  • Coatomer Protein
  • Dipeptides
  • Gene Products, nef
  • Microtubule-Associated Proteins
  • nef Gene Products, Human Immunodeficiency Virus