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- Title
PTPN2 Regulates the Interferon Signaling and Endoplasmic Reticulum Stress Response in Pancreatic β-Cells in Autoimmune Diabetes.
- 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.
- 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 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.
- Subjects
RESEARCH; ANIMAL experimentation; RESEARCH methodology; TYPE 1 diabetes; APOPTOSIS; EVALUATION research; ISLANDS of Langerhans; INTERFERONS; COMPARATIVE studies; ESTERASES; MICE
- Publication
Diabetes, 2022, Vol 71, Issue 4, p653
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db21-0443