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

posted on 2022-01-19, 15:31 authored by Bernat Elvira, Valerie Vandenbempt, Julia Bauzá-Martinez, Raphaël Crutzen, Javier Negueruela, Hazem Ibrahim, Matthew L. Winder, Manoja K. Brahma, Beata Vekeriotaite, Pieter-Jan Martens, Sumeet Pal Singh, Fernando Rossello, Pascale Lybaert, Timo Otonkoski, Conny Gysemans, Wei Wu, Esteban N. Gurzov
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.


This work was supported by a Fonds National de la Recherche Scientifique (FNRS)-MIS grant (33650793), a European Research Council (ERC) Consolidator grant METAPTPs (GA817940), a JDRF Career Development Award (CDA-2019-758-A-N).