PTPN22-CD45 dual phosphatase retrograde feedback enhances TCR signaling and autoimmunity.

ABSTRACT: Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) is encoded by a gene strongly associated with lupus and other autoimmune diseases. PTPN22 regulates T cell receptor (TCR) signaling through dephosphorylation of the kinases lymphocyte-specific protein tyrosine kinase (LCK) and zeta-chain-associated protein kinase 70 (ZAP70). The regulation of PTPN22 remains poorly understood. Here, we identify PTPN22 Ser⁴⁴⁹ as a protein kinase A phosphorylation site, which is triggered by TCR engagement and is hyperphosphorylated in lupus peripheral blood cells. PTPN22 Ser⁴⁴⁹ phosphorylation selectively lowered the affinity of PTPN22 for ZAP70 versus LCK but also indirectly suppressed inhibitory LCK Tyr¹⁹² phosphorylation through a ZAP70-CD45 signaling axis. The resu

SUBMITTER: Yang S 

PROVIDER: S-EPMC12412669 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature