PTPN22-CD45 dual phosphatase retrograde feedback enhances TCR signaling and autoimmunity
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 Ser<sup>449</sup> as a protein kinase A phosphorylation site, which is triggered by TCR engagement and is hyperphosphorylated in lupus peripheral blood cells. PTPN22 Ser<sup>449</sup> phosphorylation selectively lowered the affinity of PTPN22 for ZAP70 versus LCK but also indirectly suppressed inhibitory LCK Tyr<sup>192</sup> phosphorylation through a ZAP70-CD45 signaling axis. The resulting dephosphorylation of LCK Tyr<sup>192</sup> not only enhanced TCR signaling but also modulated pathway activation downstream the TCR. In vivo loss of PTPN22 Ser<sup>449</sup> phosphorylation reduced T cell responses and suppressed experimental lupus nephritis. These results suggest that PTPN22 Ser<sup>449</sup> phosphorylation promotes a CD45-mediated retrograde ZAP70-LCK feedback loop that enhances T cell responses and promotes autoimmunity.
Authors
- Yuan Zhan (ORCID: https://orcid.org/0009-0001-2383-0408)
- Leigh‐Ana Rossitto (ORCID: https://orcid.org/0000-0002-7744-3630)
- Q. Chen
- Nunzio Bottini (ORCID: https://orcid.org/0000-0001-9025-7501)
- Shen K. Yang (ORCID: https://orcid.org/0000-0002-4983-6787)
- Shu‐Wha Lin (ORCID: https://orcid.org/0000-0001-6748-5581)
- Caroline A. Jefferies (ORCID: https://orcid.org/0000-0002-8879-6722)
- Richard I. Ainsworth (ORCID: https://orcid.org/0000-0002-3350-5692)
- W. T. Johnson (ORCID: https://orcid.org/0000-0002-0810-6454)
- Eugenio Santelli (ORCID: https://orcid.org/0000-0002-8739-2750)
- Stephanie M. Stanford (ORCID: https://orcid.org/0000-0003-0934-5462)
- I‐Shing Yu (ORCID: https://orcid.org/0000-0002-2369-5816)
- M Yamashita (ORCID: https://orcid.org/0000-0001-6221-8900)
- Daniel J. Wallace (ORCID: https://orcid.org/0000-0002-2502-1372)
- Nisarg J. Shah
- Inhee Choi (ORCID: https://orcid.org/0000-0001-7884-1764)
- Myungja Ro
- Carlos G. Gonzalez (ORCID: https://orcid.org/0000-0002-4673-4048)
- David J. Gonzalez (ORCID: https://orcid.org/0000-0003-1423-5970)
- Chuling Zhuang (ORCID: https://orcid.org/0009-0007-0859-9491)
- Jonathan D. Yoshihara
Institutions
- Cedars-Sinai Medical Center (US)
- National Taiwan University (TW)
- University of California San Diego (US)
- National Taiwan University Hospital (TW)
- Taipei Medical University (TW)
Publication Details
- Journal
- Science Advances
- Published
- 2025-09-05
- DOI
- https://doi.org/10.1126/sciadv.adw2568
- Primary Topic
- Protein Tyrosine Phosphatases
- Type
- article
- Field-Weighted Citation Impact
- 0.00