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IGF2BP3 regulates RNA metabolism during unfolded protein response [IGF2BP3 cells]

ABSTRACT: Accumulation of misfolded proteins in the endoplasmic reticulum (ER) perturbs cellular homeostasis and leads to pathological conditions termed ER stress. The Unfolded Protein Response (UPR) is a highly conserved signaling cascade that maintains ER homeostasis. While the transcriptional response is paramount for UPR signaling, several mRNAs are regulated at the posttranscriptional level, yet how this is achieved remains poorly understood. Here, we show that a highly conserved RNA-binding protein, IGF2BP3, interacts with transcripts encoding for the UPR target genes and regulates the UPR signaling. During ER stress, IGF2BP3 destabilized most of its targets, including the UPR target RNAs. On the other hand, IGF2BP3 stabilized a subset of mRNAs encoding for transcription regulators through this indirectly regulated transcription of the UPR target genes. This feedback loop allows IGF2BP3 to elevate the levels of stress response genes while leading to the degradation of other transcripts during ER stress. Our results reveal a novel IGF2BP3-driven gene regulatory network contributing to cellular adaptation to ER stress.

ORGANISM(S): Homo sapiens

PROVIDER: GSE289481 | GEO | 2026/07/23

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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IGF2BP3 regulates RNA metabolism during unfolded protein response [IGF2BP3 cells]

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