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A novel gain-of-function phosphorylation site modulates PTPN22 inhibition of TCR signaling.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2024 Jun; Vol. 300 (6), pp. 107393. Date of Electronic Publication: 2024 May 21. - Publication Year :
- 2024
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Abstract
- Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) is encoded by a major autoimmunity gene and is a known inhibitor of T cell receptor (TCR) signaling and drug target for cancer immunotherapy. However, little is known about PTPN22 posttranslational regulation. Here, we characterize a phosphorylation site at Ser <superscript>325</superscript> situated C terminal to the catalytic domain of PTPN22 and its roles in altering protein function. In human T cells, Ser <superscript>325</superscript> is phosphorylated by glycogen synthase kinase-3 (GSK3) following TCR stimulation, which promotes its TCR-inhibitory activity. Signaling through the major TCR-dependent pathway under PTPN22 control was enhanced by CRISPR/Cas9-mediated suppression of Ser <superscript>325</superscript> phosphorylation and inhibited by mimicking it via glutamic acid substitution. Global phospho-mass spectrometry showed Ser <superscript>325</superscript> phosphorylation state alters downstream transcriptional activity through enrichment of Swi3p, Rsc8p, and Moira domain binding proteins, and next-generation sequencing revealed it differentially regulates the expression of chemokines and T cell activation pathways. Moreover, in vitro kinetic data suggest the modulation of activity depends on a cellular context. Finally, we begin to address the structural and mechanistic basis for the influence of Ser <superscript>325</superscript> phosphorylation on the protein's properties by deuterium exchange mass spectrometry and NMR spectroscopy. In conclusion, this study explores the function of a novel phosphorylation site of PTPN22 that is involved in complex regulation of TCR signaling and provides details that might inform the future development of allosteric modulators of PTPN22.<br />Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.<br /> (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Humans
Phosphorylation
Gain of Function Mutation
T-Lymphocytes metabolism
T-Lymphocytes immunology
Jurkat Cells
HEK293 Cells
Receptors, Antigen, T-Cell metabolism
Receptors, Antigen, T-Cell immunology
Protein Tyrosine Phosphatase, Non-Receptor Type 22 genetics
Protein Tyrosine Phosphatase, Non-Receptor Type 22 metabolism
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 300
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 38777143
- Full Text :
- https://doi.org/10.1016/j.jbc.2024.107393