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

• Published in: Diabetes (New York, N.Y.) Vol. 71; no. 4; pp. 653 - 668
• Main Authors: Elvira, Bernat, Vandenbempt, Valerie, Bauzá-Martinez, Julia, Crutzen, Raphaël, Negueruela, Javier, Ibrahim, Hazem, Winder, Matthew L, Brahma, Manoja K, Vekeriotaite, Beata, Martens, Pieter-Jan, Singh, Sumeet Pal, Rossello, Fernando, Lybaert, Pascale, Otonkoski, Timo, Gysemans, Conny, Wu, Wei, Gurzov, Esteban N
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01-04-2022
• Subjects: Age; Animals; Apoptosis - genetics; Autoimmune diseases; Autoimmunity; Beta cells; Calcium; CD3 antigen; Cell death; Cellular stress response; Diabetes; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - metabolism; Endoplasmic reticulum; Endoplasmic Reticulum Stress - physiology; Humans; Hyperglycemia; Insulin-Secreting Cells - metabolism; Interferon; Interferon-gamma - pharmacology; Interleukin 1; Interleukin 1 receptor antagonist; Mice; Mice, Inbred NOD; Monoclonal antibodies; Pancreas; Protein folding; Protein Tyrosine Phosphatase, Non-Receptor Type 2 - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 2 - metabolism; Proteins; PTPN2 protein; Stem cells; Tyrosine
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db21-0443

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.