PTPN2 Regulates the Interferon Signaling and Endoplasmic Reticulum Stress Response in Pancreatic β-Cells in Autoimmune Diabetes

Abstract

Type 1 diabetes (T1D) results from autoimmune destruction of β-cells in the pancreas. Protein tyrosine phosphatases (PTPs) are candidate genes for T1D and play a key role in autoimmune disease development and β-cell dysfunction. Here, we assessed the global protein and individual PTP profiles in the pancreas from early onset non-obese diabetic (NOD) mice treated with an anti-CD3 monoclonal antibody and interleukin-1 receptor antagonist. The treatment reversed hyperglycemia and we observed enhanced expression of PTPN2, a PTP family member and T1D candidate gene, and endoplasmic reticulum (ER) chaperones in the pancreatic islets. To address the functional role of PTPN2 in β-cells, we generated PTPN2-deficient human stem cell-derived β-like and EndoC-βH1 cells. Mechanistically, we demonstrated that PTPN2 inactivation in β-cells exacerbates type I and type II interferon signaling networks and the potential progression towards autoimmunity. Moreover, we established the capacity of PTPN2 to positively modulate the Ca2+-dependent unfolded protein response and ER stress outcome in β-cells. Adenovirus-induced overexpression of PTPN2 partially protected from ER-stress induced β-cell death. Our results postulate PTPN2 as a key protective factor in β-cells during inflammation and ER stress in autoimmune diabetes.

Stem-Cell-Derived β-Like Cells with a Functional PTPN2 Knockout Display Increased Immunogenicity

“…The gene set enrichment analysis shows the significant upregulation of hallmark interferon gamma response genes, oxidative phosphorylation, and IL-6, JAK, and STAT3 signaling ( Figure 3 B–D) in the PTPN2 KO cells compared to WT, thereby verifying recent results showing the upregulation of interferon gamma signaling after PTPN2 knock down in different beta cell models [ 27 ].…”

“…PTPN2 has also been shown to modulate IFN-γ signal transduction in the beta cell and regulate cytokine-induced apoptosis [ 26 ]. Functionally, PTPN2 deficiency has been shown to exacerbate type I and II interferon-signaling networks [ 27 ] and knockdown of PTPN2 in EndoC-βH1 human-beta-like cells demonstrates an amplification of an inflammatory response via STAT1 phosphorylation. We sought to build upon these findings by investigating the effects of a functional PTPN2 knockout in sBC using detailed phenotypic analyses and novel co-culture systems by employing autoreactive T cell transductants targeting sBC.…”

Whole-genome CRISPR screening identifies genetic manipulations to reduce immune rejection of stem cell-derived islets

“…Downstream to STAT1 is the transcription factor IRF1, which has anti-inflammatory effects in β cells through the induction of SOCS1 ( Moore et al., 2011 ). SOCS1 and PTPN2 are negative regulators of cytokine signaling ( Chong et al., 2002 ; Elvira et al., 2022 ; Moore et al., 2009 ) and are both associated with T1D risk loci ( Onengut-Gumuscu et al., 2015 ; Ram and Morahan, 2017 ). Previous reports have shown that SOCS1 overexpression in NOD mice islets prevent diabetes ( Flodstrom-Tullberg et al., 2003 ), and delays allogeneic islet graft rejection in mouse models ( Solomon et al., 2011 ).…”

Ligament Alteration in Diabetes Mellitus

“…Endoplasmic reticulum (ER) stress activated by overstimulation mainly involves three unfolded protein-response signalling pathways, including activating transcription factor 6 (ATF6) pathway, double-stranded RNA-activated protein kinase (PKR)-like endoplasmic reticulum kinase (PERK) pathway, and inositol-requiring enzyme 1 (IRE1) pathway. While moderate ER stress can effectively protect the body, excessive ER stress causes degeneration [ 48 , 49 ]. Song X et al evidenced that ER causes apoptosis in PDL and vascular calcification in a rat model [ 50 ].…”

“…In the previous study of Tan J et al, ER stress was also found to reduce the osteogenic differentiation ability of PDL when influenced by tumour necrosis factor-α [ 46 ]. Both indicate that an inflammatory microenvironment causes drastic interruption throughout the physiological functioning of cell mechanisms in ligaments [ 49 , 51 ].…”