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

par Elvira Jimenez, Bernat ;Vandenbempt, Valerie ;Bauzá-Martinez, J.;Crutzen, Raphaël ;Negueruela, Javier;Ibrahim, Hazem;Winder, Matthew ML;Brahma, Manoja Kumar ;Vekeriotaite, Beata ;Martens, Pieter-Jan;Singh, Sumeet Pal ;Rossello, Fernando;Lybaert, Pascale ;Otonkoski, Timo;Gysemans, Conny;Wu, Wei;Gurzov, Esteban Nicolas
Référence Diabetes (New York, N.Y.)
Publication Publié, 2022-01-01

Article révisé par les pairs

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Résumé :

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.