A novel PTPN2 protein isoform differentially regulates Inflammation

The presence of a single nucleotide polymorphism (SNP) in the PTPN2 gene has been associated with autoimmune diseases, including inflammatory bowel disease (IBD). This SNP is predicted to enhance the PTPN2 isoform 4 (PTPN2.4) expression. Our bulk RNAseq data showed an increased expression of PTPN2.4 in Crohn’s disease patients. To examine the specific functions of each PTPN2 isoform, we established stable cell lines with overexpressed isoforms. Our findings revealed that the overexpression of PTPN2 isoform 2, widely recognized isoform, led to a reduction of pro-inflammatory cytokines (TNF-a, IL-1b, IL-6) induced by LPS. Oppositely, the overexpression of PTPN2.4 resulted in an increase in TNF-a secretion in myeloid cells. Knockdown of PTPN2.4 in human myeloid cells decreased pro-inflammatory cytokines. We also found that the differential subcellular localization of PTPN2.4, which is excluded from the nucleus, and PTPN2.2, which is in both the nucleus and cytoplasm, contributes to their distinct phenotypic responses. Mutations in the nuclear exclusion sequence (NES) of PTPN2.4 abolished its unique localization and function. Finally, proteomic analysis identified PTPN2.4-specific binding partners. In summary, this study demonstrates that PTPN2.4 differentially regulates inflammatory cytokines due to its distinct subcellular localization and substrate selectivity. Targeting pathogenic PTPN2.4 could potentially attenuate inflammatory responses in IBD patients.