PTPN2 Regulates the Interferon Signaling and Endoplasmic Reticulum Stress Response in Pancreatic β-Cells in Autoimmune Diabetes
PTPN2 Regulates the Interferon Signaling and Endoplasmic Reticulum Stress Response in Pancreatic β-Cells in Autoimmune Diabetes
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DOI：
10.2337/db21-0443
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发表时间：
2022-04-01
期刊：
影响因子：
7.7
通讯作者：
Gurzov, Esteban N.
中科院分区：
文献类型：
--
作者：
Elvira, Bernat;Vandenbempt, Valerie;Gurzov, Esteban N.
1型糖尿病（T1 D）是由胰腺中β细胞的自身免疫性破坏引起的。蛋白酪氨酸磷酸酶（PTPs）是T1 D的候选基因，在自身免疫性疾病的发展和β细胞功能障碍中起关键作用。在这里，我们评估了全球蛋白质和个人PTP档案在非肥胖小鼠胰腺早发性糖尿病（NOD）小鼠治疗抗CD 3单克隆抗体和白细胞介素-1受体拮抗剂。治疗逆转了高血糖，我们观察到PTPN 2（PTP家族成员和T1 D候选基因）和内质网（ER）伴侣在胰岛中的表达增强。为了解决PTPN 2在β细胞中的功能作用，我们产生了PTPN 2缺陷的人干细胞衍生的β样和EndoC-β H1细胞。从机制上讲，我们证明β细胞中的PTPN 2失活加剧了I型和II型干扰素信号传导网络以及向自身免疫的潜在进展。此外，我们建立了PTPN 2正向调节β细胞中Ca 2+依赖性未折叠蛋白反应和ER应激结果的能力。腺病毒诱导的PTPN 2过表达部分保护了ER应激诱导的β细胞死亡。我们的研究结果假设PTPN 2是自身免疫性糖尿病炎症和ER应激过程中β细胞的关键保护因子。
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.