期刊
DIABETES
卷 71, 期 4, 页码 653-668出版社
AMER DIABETES ASSOC
DOI: 10.2337/db21-0443
关键词
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资金
- Fonds National de la Recherche Scientifique (FNRS)-MIS grant [33650793]
- European Research Council Consolidator grant METAPTPs [GA817940]
- JDRF Career Development Award [CDA2019-758-A-N]
- FNRS CR postdoctoral fellowship [34769436]
- FNRS PhD Aspirant scholarship
- mandat d'impulsion scientifique - mobilite Ulysse (MISU) - FNRS [34772792]
This study assessed the PTP protein profiles in the pancreas of type 1 diabetes patients and found that PTPN2 plays a protective role in beta-cells. Inactivation of PTPN2 in beta-cells exacerbates interferon signaling pathways and may lead to autoimmune progression.
Type 1 diabetes (T1D) results from autoimmune destruction of beta-cells in the pancreas. Protein tyrosine phosphatases (PTPs) are candidate genes for T1D and play a key role in autoimmune disease development and beta-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 beta-cells, we generated PTPN2-deficient human stem cell-derived beta-like and EndoC-beta H1 cells. Mechanistically, we demonstrated that PTPN2 inactivation in beta-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 beta-cells. Adenovirus-induced overexpression of PTPN2 partially protected from ER stress-induced beta-cell death. Our results postulate PTPN2 as a key protective factor in beta-cells during inflammation and ER stress in autoimmune diabetes.
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