Cyclophilin A associates with and regulates the activity of ZAP70 in TCR/CD3-stimulated T cells

Nikhil Ponnoor Anto, Awadhesh Kumar Arya, Amitha Muraleedharan, Jakeer Shaik, Pulak Ranjan Nath, Etta Livneh, Zuoming Sun, Alex Braiman, Noah Isakov

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

The ZAP70 protein tyrosine kinase (PTK) couples stimulated T cell antigen receptors (TCRs) to their downstream signal transduction pathways and is sine qua non for T cell activation and differentiation. TCR engagement leads to activation-induced post-translational modifications of ZAP70, predominantly by kinases, which modulate its conformation, leading to activation of its catalytic domain. Here, we demonstrate that ZAP70 in TCR/CD3-activated mouse spleen and thymus cells, as well as human Jurkat T cells, is regulated by the peptidyl-prolyl cis–trans isomerase (PPIase), cyclophilin A (CypA) and that this regulation is abrogated by cyclosporin A (CsA), a CypA inhibitor. We found that TCR crosslinking promoted a rapid and transient, Lck-dependent association of CypA with the interdomain B region, at the ZAP70 regulatory domain. CsA inhibited CypA binding to ZAP70 and prevented the colocalization of CypA and ZAP70 at the cell membrane. In addition, imaging analyses of antigen-specific T cells stimulated by MHC-restricted antigen-fed antigen-presenting cells revealed the recruitment of ZAP70-bound CypA to the immunological synapse. Enzymatically active CypA downregulated the catalytic activity of ZAP70 in vitro, an effect that was reversed by CsA in TCR/CD3-activated normal T cells but not in CypA-deficient T cells, and further confirmed in vivo by FRET-based studies. We suggest that CypA plays a role in determining the activity of ZAP70 in TCR-engaged T cells and impact on T cell activation by intervening with the activity of multiple downstream effector molecules.

Original languageEnglish
Article number7 (2023)
JournalCellular and Molecular Life Sciences
Volume80
Issue number1
DOIs
StatePublished - 10 Dec 2022

Keywords

  • Cyclophilin A
  • Cyclosporin A
  • Immunophilin
  • Isomerase
  • T cell activation
  • ZAP70

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Cellular and Molecular Neuroscience
  • Cell Biology

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