IGF2BP3 regulates RNA metabolism during unfolded protein response

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.