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Uncontrolled endoplasmic reticulum stress response leads to pancreatic beta cell death via JNK andp53

ABSTRACT: Endoplasmic reticulum (ER) stress is a cause of beta cell death in both T1D and T2D. However, no therapeutics to reduce beta cell death have been approved, in part because molecular mechanisms driving beta cell death during ER stress are insufficiently defined. GRP78, an ER chaperone, is the critical regulator of unfolded protein response (UPR) stress response pathways. GRP78 binds and suppresses UPR initiators during the unstressed state, releasing them to promote UPR activation during stress. To study pathways causing beta cell decompensation during active ER stress and the related stress response, we engineered mice genetically lacking GRP78 in pancreatic beta cells. GRP78 deletion caused acute insulin deficient diabetes in pups before weaning, with reduced beta cell mass due to increased apoptosis. Molecular studies identified deregulated UPR, specifically IRE1 activity, as driving cell death. Unbiased and targeted analyses outline a pathway in which JNK activity downstream of IRE1 kinase leads to p53 activation to mediate beta cell death during ER stress. Remarkably, in vivo JNK inhibition reduced beta cell death in two distinct ER stress diabetes models. In human beta cells, inhibitors of JNK and of p53 were both effective to improve beta cell survival in the face of ER stress. Our findings provide insight into mechanisms causing beta cell death and outline possible therapeutic targets to preserve insulin secretory capacity in the face of ER stress.

ORGANISM(S): Mus musculus

PROVIDER: GSE282680 | GEO | 2026/05/27

REPOSITORIES: GEO

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Project description:Bronchopulmonary dysplasia (BPD), a chronic lung disease of prematurity, has been linked to endoplasmic reticulum (ER) stress. To investigate a causal role for ER stress in BPD pathogenesis, we generated mice (cGrp78f/f) with lung epithelial cell-specific knockout (KO) of Grp78, a gene encoding the ER chaperone 78-kDa glucose-regulated protein (GRP78), a master regulator of ER homeostasis and the unfolded protein response (UPR). Lung epithelial-specific Grp78 KO disrupted lung morphogenesis, causing developmental arrest, increased alveolar epithelial type II cell apoptosis and decreased surfactant protein and type I cell marker expression in perinatal lungs. cGrp78f/f pups died immediately after birth, likely due to respiratory distress. Importantly, Grp78 KO triggered UPR activation with marked induction of pro-apoptotic transcription factor C/EBP homologous protein (CHOP). Increased expression of genes involved in oxidative stress and cell death and decreased expression of genes encoding antioxidant enzymes suggest a role for oxidative stress in alveolar epithelial cell (AEC) apoptosis. Increased Smad3 phosphorylation and expression of transforming growth factor-Î² (TGF-Î²)/Smad3 targets Cdkn1a (encoding p21) and Gadd45a suggest that interactions among the apoptotic arm of the UPR, oxidative stress and TGF-Î²/Smad signaling pathways contribute to Grp78 KO-induced AEC apoptosis and developmental arrest. Chemical chaperone taursodeoxycholic acid reduced UPR activation and apoptosis in cGrp78f/f lungs cultured ex vivo, confirming a role for ER stress in observed AEC abnormalities. These results demonstrate a key role for GRP78 in AEC survival and gene expression during lung development through modulation of ER stress and suggest the UPR as a potential therapeutic target in BPD. Whole-genome expression profiling was performed using MouseRef-8 v2.0 Expression BeadChips (Illumina) on RNA isolated from lungs of four Grp78f/f and three cGrp78f/f mice at E18.

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Uncontrolled endoplasmic reticulum stress response leads to pancreatic beta cell death via JNK andp53

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