A novel gain-of-function phosphorylation site modulates PTPN22 inhibition of TCR signaling
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1102292 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28742536_1.fastq.gz | Fastqsanger.gz | |||
| SRR28742536_2.fastq.gz | Fastqsanger.gz | |||
| SRR28742537_1.fastq.gz | Fastqsanger.gz | |||
| SRR28742537_2.fastq.gz | Fastqsanger.gz | |||
| SRR28742538_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 96 |
Similar Datasets
Project description:Protein Tyrosine Phosphatase Non-receptor 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 post-translational regulation. Here we characterize a phosphorylation site at Ser325 situated C-terminal to the catalytic domain of PTPN22, and its roles in altering protein function. Signaling through the major TCR-dependent pathway under PTPN22 control was enhanced by CRISPR/Cas9 mediated suppression of Ser325 phosphorylation and inhibited by mimicking it via glutamic acid substitution. Next-generation sequencing (NGS) revealed it differentially regulates the expression of chemokines and T cell activation pathways. In conclusion, this study explores the function of a novel phosphorylation site of PTPN22 that is involved in complex regulation of TCR signaling .
2024-07-17 | GSE264373 | GEO
Project description: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 Ser325 situated C terminal to the catalytic domain of PTPN22 and its roles in altering protein function. In human T cells, Ser325 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 Ser325 phosphorylation and inhibited by mimicking it via glutamic acid substitution. Global phospho-mass spectrometry showed Ser325 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 Ser325 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.
| S-EPMC11237943 | biostudies-literature
Project description:Protein Tyrosine Phosphatase Non-receptor type 22 (PTPN22) is encoded by a major autoimmunity gene and is a known inhibitor of T cell receptor (TCR) signaling for cancer immunotherapy. However, little is known about PTPN22 phosphorylation in tumor infiltrating T cells. Here we characterize a phosphorylation site at Ser452 situated in the interdomain of PTPN22, and its roles in altering T cell function and tumor growth. Tumor infiltrating CD8+ T cells from PepWT or PepS452A mice were collected and subjected to next-generation sequencing (NGS). The results revealed it differentially regulates the genes expression of metabolic process, cytokine prodcution and adaptive immunity etc. This study explores the function of a novel phosphorylation site of PTPN22 that is involved in complex regulation of CD8+ T cell activity, fuctions and tumor growth.
2025-04-02 | GSE263092 | GEO
Project description:3x FLAG tagged PTPN22 were immunoprecipitated from Jurkat cells stimulated by TCR for 5min, and the proteins were eluted by FLAG peptides. This study aims to explore the phosphorylation sites on PTPN22 phosphatase, identifying two phosphorylation sites Ser325 and Ser449.
2023-12-21 | MSV000093717 | MassIVE
Project description:Protein Tyrosine Phosphatase Non-receptor type 22 (PTPN22) is encoded by a major autoimmunity gene and is a known inhibitor of T cell receptor (TCR) signaling. PTPN22 Ser449 is a novel phosphorylation site. Here we used optimized coding sequences (CDS) of PTPN22 WT or S449A eukaryotic expression vectors with N-terminal mEGFP and electroporated into either J.Lck WT or J.Lck Y192F cells to analyze the relationship between PTPN22 Ser449 phosphorylaion and Lck Tyr192 phosphorylaion by CITE seq.
2025-04-25 | GSE265961 | GEO
Project description:Phosphorylation sites of PTPN22 induced by Calyculin A treatment were identified by LC-MS
2021-09-08 | PXD016103 | Pride
Project description:The presence of the PTPN22 risk variant (1858T) is associated to several autoimmune diseases including rheumatoid arthritis (RA). Despite a number of studies exploring the function of PTPN22 in T cells, the exact impact of the PTPN22 risk variant on T cell function in humans is still unclear. In this study, using RNA sequencing, we show that, upon TCR-activation, naïve CD4+ T cells carrying two PTPN22 risk alleles overexpress a limited number of genes including CFLAR and 4-1BB important for cytotoxic T cell differentiation. Moreover, an increased number of cytotoxic EOMES+ CD4+ T cells were observed in PTPN22 risk allele carriers, which negatively correlated with a decreased number of naïve T cells in older individuals. No difference in the frequency of other CD4+ T cell subsets (Th1, Th17, Tfh, Treg) was observed in PTPN22 risk allele carriers and Treg suppressive capacity was not altered. Finally, in synovial fluids of RA patients, an accumulation of EOMES+ CD4+ T cells was observed with a more pronounced production of Perforin-1 in PTPN22 risk allele carriers. Altogether, our data provide a novel mechanism of action of PTPN22 risk variant on CD4+ T-cell differentiation and identify EOMES+ CD4+ T cell as a relevant T cell subset in RA.
2018-02-27 | GSE94859 | GEO
Project description:PTPN22, a modifier of T cell receptor signaling, and reactive oxygen species are major players in the regulation of chronic autoimmune diseases. As with all protein tyrosine phosphatases the activity of PTPN22 is redox regulated, but if or how such regulation can modulate inflammatory pathways in vivo is not known. To determine this, we created a mouse with a cysteine-to-serine mutation at position 129 in PTPN22 (C129S), a residue proposed to alter the redox regulatory properties of PTPN22 by forming a disulfide with the catalytic C227 residue. The C129S mutant mouse showed a stronger T cell-dependent inflammatory response due to enhanced TCR signaling and activation of T cells. Activity assays with purified proteins suggest that the functional results can be explained by an increased sensitivity to oxidation of the C129S mutated PTPN22 protein. We also observed that the disulfide of native PTPN22 can be directly reduced by the thioredoxin system, while the C129S mutant lacking this disulfide was less amenable to reductive reactivation. In conclusion, we show in the mouse that the non-catalytic C129 residue of PTPN22 modulates its redox regulatory properties, and that oxidation-prone PTPN22 leads to increased severity in the development of T cell-dependent autoimmunity.
2022-03-23 | PXD025319 | Pride
Project description:Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene segregates with most autoimmune diseases; its risk allele encodes overactive PTPN22 phosphatases that alter B cell receptor (BCR) signaling potentially involved in the regulation of central B cell tolerance. To assess whether PTPN22 risk allele affects the removal of developing autoreactive B cells, we tested by ELISA the reactivity of recombinant antibodies isolated from single B cells from asymptomatic healthy individuals carrying one or two PTPN22 risk allele(s). We found that new emigrant/transitional and mature naive B cells from PTPN22 risk allele carriers contained high frequencies of autoreactive clones compared to non-carrier control donors. Hence, a single PTPN22 risk allele has a dominant effect on altering autoreactive B cell counterselection, suggesting that early B cell tolerance checkpoint defects precede the onset of autoimmunity. In addition, gene array experiments comparing mature naïve B cells from healthy individuals carrying or not PTPN22 risk allele(s) revealed that the strength of association of PTPN22 for autoimmunity, second in importance only to the MHC, may not only be due to BCR signaling alteration but also to the regulation of other genes, which themselves have also been identified as involved in the development of autoimmune diseases. The PTPN22 risk allele is a single nucleotide change (cytidine to thymidine) at residue 1858, which results in a single amino acid substitution from arginine to tryptophan at position 620 of the PTPN22/Lyp protein.
2010-10-16 | GSE24736 | GEO
Project description:LQF of 3x FLAG PTPN22 WT Jurkat cells compared to S325A and S325E KI mutant Jurkat cells. WT or KI lines were stimulated with or without TCR engagement for 5 min.
2023-12-21 | MSV000093718 | MassIVE