Dual regulation of the unfolded protein response by IGF2BP3 during ER stress.

Misfolded protein accumulation in the endoplasmic reticulum (ER) perturbs cellular homeostasis, causing pathological ER stress. While a transcriptional response is paramount for the unfolded protein response (UPR), which counters ER protein stress, multiple UPR-linked mRNAs are posttranscriptionally regulated. However, the mechanisms mediating this regulation remain unclear. Here, we reveal specific interactions between the conserved RNA-binding protein IGF2BP3 and transcripts encoding UPR effectors. During ER stress, IGF2BP3 destabilizes many of its target transcripts, including UPR effectors. Mechanistically, ER stress enhances IGF2BP3's association with the mRNA decapping complex and the ER stress sensor RNase IRE1, which correlates with a shift toward mRNA destabilization. Unexpectedly, prolonged depletion of IGF2BP3 inhibits the UPR via decreased transcription of UPR target genes. Together, our findings suggest that IGF2BP3 contributes to proteostasis during ER stress through a dual mechanism: directly promoting mRNA degradation to reduce translation and folding burden and indirectly supporting transcriptional activation of the UPR.