ZAP-70 is a cytoplasmic tyrosine kinase essential for T cell-mediated immune responses. Upon engagement of the T cell receptor, ZAP-70 is quickly recruited to the specialized plasma membrane domains, becomes activated and released to phosphorylate its laterally segregated downstream targets. A shift in ZAP-70 distribution at the plasma membrane is recognized as a critical step in T cell receptor signal transduction and amplification. However, the molecular mechanism supporting

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... ent plasma membrane compartmentalization of ZAP-70 remains poorly understood. In this study, we identified previously uncharacterized reversible lipidation (S-acylation) of ZAP-70. We found that this post-translational modification of ZAP-70 is dispensable for its enzymatic activity. However, the lipidation-deficient mutant of ZAP-70 failed to propagate the T cell receptor signaling cascade suggesting that S-acylation is essential for ZAP-70 interaction with its protein substrates. The kinetics of ZAP-70 S-acylation were consistent with early T cell signaling events indicating that agonist-induced S-acylation is a part of the signaling mechanism controlling T cell activation and function.