Nef induces CD4 endocytosis: requirement for a critical dileucine motif in the membrane-proximal CD4 cytoplasmic domain.
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.
Aiken
C
C
Infectious Disease Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037-1099.
Konner
J
J
Landau
N R
NR
Lenburg
M E
ME
Trono
D
D
D000595:Amino Acid Sequence; D015704:CD4 Antigens / Q000378:metabolism*; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D015536:Down-Regulation; D004705:Endocytosis; D015693:Gene Products, nef / Q000502:physiology*; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D007930:Leucine / Q000737:chemistry; D008247:Lysosomes / Q000378:metabolism; D008969:Molecular Sequence Data; D009226:Myristates / Q000378:metabolism; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D054311:nef Gene Products, Human Immunodeficiency Virus
D015704:CD4 Antigens; D015693:Gene Products, nef; D009226:Myristates; D054311:nef Gene Products, Human Immunodeficiency Virus; D007930:Leucine