T cell receptor-dependent S-acylation of ZAP-70 controls activation of T cells

J Biol Chem. 2021 Jan-Jun:296:100311. doi: 10.1016/j.jbc.2021.100311. Epub 2021 Jan 19.


ZAP-70 is a tyrosine kinase essential for T cell immune responses. Upon engagement of the T cell receptor (TCR), ZAP-70 is recruited to the specialized plasma membrane domains, becomes activated, and is released to phosphorylate its laterally segregated targets. A shift in ZAP-70 distribution at the plasma membrane is recognized as a critical step in TCR signal transduction and amplification. However, the molecular mechanism supporting stimulation-dependent plasma membrane compartmentalization of ZAP-70 remains poorly understood. In this study, we identified previously uncharacterized lipidation (S-acylation) of ZAP-70 using Acyl-Biotin Exchange assay, a technique that selectively captures S-acylated proteins. We found that this posttranslational modification of ZAP-70 is dispensable for its enzymatic activity. However, the lipidation-deficient mutant of ZAP-70 failed to propagate the TCR pathway suggesting that S-acylation is essential for ZAP-70 interaction with its protein substrates. The kinetics of ZAP-70 S-acylation were consistent with TCR signaling events indicating that agonist-induced S-acylation is a part of the signaling mechanism controlling T cell activation and function. Taken together, our results suggest that TCR-induced S-acylation of ZAP-70 can serve as a critical regulator of T cell-mediated immunity.

Keywords: S-acylation; T cell; acyltransferase; palmitoylation; signal transduction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acylation / genetics
  • Acyltransferases / chemistry
  • Acyltransferases / genetics
  • Cell Membrane / chemistry
  • Cell Membrane / genetics
  • Gene Expression Regulation, Enzymologic / genetics
  • Humans
  • Immunity, Cellular / genetics*
  • Immunity, Cellular / immunology
  • Lipoylation / genetics
  • Mutation / genetics
  • Protein Processing, Post-Translational / genetics
  • Receptors, Antigen, T-Cell / genetics*
  • Receptors, Antigen, T-Cell / immunology
  • Signal Transduction / genetics
  • Substrate Specificity / genetics
  • T-Lymphocytes / chemistry
  • T-Lymphocytes / immunology*
  • ZAP-70 Protein-Tyrosine Kinase / chemistry
  • ZAP-70 Protein-Tyrosine Kinase / genetics*


  • Receptors, Antigen, T-Cell
  • Acyltransferases
  • ZAP-70 Protein-Tyrosine Kinase