CD81 associates with 14-3-3 in a redox-regulated palmitoylation-dependent manner

J Biol Chem. 2004 May 7;279(19):19401-6. doi: 10.1074/jbc.M312626200. Epub 2004 Feb 13.


As a member of the tetraspanin superfamily of proteins, CD81 has been linked to a number of biologic functions including cellular proliferation, differentiation, activation, and degranulation. As a co-receptor for hepatitis C virus, and a requirement for hepatocytes for infectivity of human Plasmodium falciparum and rodent P. yoelii sporozoite infectivity, CD81 may also play a vital role in pathology. Despite the importance of CD81 in multiple cellular functions, the molecular mechanism of action of CD81 in these processes has remained elusive. Here we report an association between CD81 and the epsilon isoform of 14-3-3, a serine/threonine-binding intracellular signaling protein. Furthermore, we provide evidence that in human, this association is influenced by the palmitoylation state of the CD81 cytoplasmic tails. We have generated a series of CD81 cysteine mutants to identify palmitoylated intracellular motifs of CD81, and reveal palmitoylation on the N- and C-terminal tails as well as the intracellular loop between transmembrane domains 2 and 3. One of these mutants lacks all five of its intracellular cysteines and therefore cannot be palmitoylated. This unpalmitoylated version of CD81 shows constitutive association with 14-3-3. Interestingly, we find that under oxidative conditions, CD81 palmitoylation is inhibited and that condition correlates with the association of CD81 and 14-3-3. These finding suggest that CD81 signaling events could be mediated by 14-3-3 adapter proteins, and these signals may be dependent on cellular redox.

Publication types

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

MeSH terms

  • 14-3-3 Proteins
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Antigens, CD / metabolism*
  • Blotting, Western
  • COS Cells
  • Cell Division
  • Cloning, Molecular
  • Cysteine / chemistry
  • Cytoplasm / metabolism
  • Electrophoresis, Polyacrylamide Gel
  • Hepatocytes / metabolism
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Jurkat Cells
  • Mice
  • Molecular Sequence Data
  • NIH 3T3 Cells
  • Oxidation-Reduction*
  • Oxidative Stress
  • Oxygen / metabolism
  • Palmitic Acid / metabolism*
  • Plasmids / metabolism
  • Precipitin Tests
  • Protein Binding
  • Protein Isoforms
  • Protein Structure, Tertiary
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Tetraspanin 28
  • Transfection
  • Tyrosine 3-Monooxygenase / metabolism*


  • 14-3-3 Proteins
  • Antigens, CD
  • CD81 protein, human
  • Cd81 protein, mouse
  • Protein Isoforms
  • Tetraspanin 28
  • Palmitic Acid
  • Hydrogen Peroxide
  • Tyrosine 3-Monooxygenase
  • Cysteine
  • Oxygen