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PTPN2 Regulates the Interferon Signaling and Endoplasmic Reticulum Stress Response in Pancreatic β-Cells in Autoimmune Diabetes.
- Source :
-
Diabetes [Diabetes] 2022 Apr 01; Vol. 71 (4), pp. 653-668. - Publication Year :
- 2022
-
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.<br /> (© 2022 by the American Diabetes Association.)
- Subjects :
- Animals
Apoptosis genetics
Endoplasmic Reticulum Stress physiology
Humans
Interferon-gamma pharmacology
Mice
Mice, Inbred NOD
Protein Tyrosine Phosphatase, Non-Receptor Type 2 genetics
Diabetes Mellitus, Type 1 metabolism
Insulin-Secreting Cells metabolism
Protein Tyrosine Phosphatase, Non-Receptor Type 2 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1939-327X
- Volume :
- 71
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Diabetes
- Publication Type :
- Academic Journal
- Accession number :
- 35044456
- Full Text :
- https://doi.org/10.2337/db21-0443