Nef induces CD4 endocytosis: requirement for a critical dileucine motif in the membrane-proximal CD4 cytoplasmic domain

Cell. 1994 Mar 11;76(5):853-64. doi: 10.1016/0092-8674(94)90360-3.


CD4 is crucial for antigen-driven helper T cell signaling and is used as receptor by the human immunodeficiency virus (HIV). The HIV early protein Nef causes a loss of CD4 from cell surfaces through a previously undefined posttranscriptional mechanism. Here, we demonstrate that Nef acts by inducing CD4 endocytosis, resulting in its degradation in lysosomes. CD4 down-regulation is strongly enhanced by the association of Nef with cell membranes through myristoylation. The study of chimeric molecules reveals that 20 membrane-proximal residues of the CD4 cytoplasmic domain are sufficient to confer Nef sensitivity. Within this region, a dileucine motif, reminiscent of an endocytosis and lysosomal targeting signal found in the CD3 gamma and delta chains, is crucial for CD4 response to Nef.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • CD4 Antigens / metabolism*
  • Cell Line
  • Cytoplasm / metabolism
  • Down-Regulation
  • Endocytosis
  • Gene Products, nef / physiology*
  • HIV-1 / metabolism*
  • Humans
  • Leucine / chemistry
  • Lysosomes / metabolism
  • Molecular Sequence Data
  • Myristates / metabolism
  • Sequence Alignment
  • Structure-Activity Relationship
  • nef Gene Products, Human Immunodeficiency Virus


  • CD4 Antigens
  • Gene Products, nef
  • Myristates
  • nef Gene Products, Human Immunodeficiency Virus
  • Leucine