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

• DOI: 10.2337/db21-0443
• Publication Date: 2022-01-19T14:01:23Z
• Authors: 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
• Keywords: 0301 basic medicine; Protein Tyrosine Phosphatase, Non-Receptor Type 2/genetics; Endocrinology, Diabetes and Metabolism; Apoptosis; Interferon-gamma; Mice; 03 medical and health sciences; Insulin-Secreting Cells/metabolism; SDG 3 - Good Health and Well-being; Mice, Inbred NOD; Apoptosis/genetics; Insulin-Secreting Cells; Taverne; Internal Medicine; Diabetes Mellitus; Diabetes Mellitus, Type 1/metabolism; Animals; Humans; Protein Tyrosine Phosphatase, Non-Receptor Type 2; 0303 health sciences; Type 1/metabolism; Interferon-gamma/pharmacology; Sciences bio-médicales et agricoles; Endoplasmic Reticulum Stress/physiology; Endoplasmic Reticulum Stress; Non-Receptor Type 2/genetics; 3. Good health; Diabetes Mellitus, Type 1; Inbred NOD; Protein Tyrosine Phosphatase

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 nonobese mice with early-onset diabetes (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 toward 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.