Misfolded protein accumulation in the endoplasmic reticulum (ER) perturbs cellular homeostasis, causing pathological ER stress. The Unfolded Protein Response (UPR) is a highly conserved signaling cascade that restores ER homeostasis by countering ER protein overload. Transcriptional response is paramount for UPR signaling and negating ER stress. While multiple UPR-linked mRNAs are post-transcriptionally regulated, the mechanisms mediating this regulation are unclear. Here, we demonstrate that the highly conserved RNA-binding protein IGF2BP3 interacts with transcripts encoding a subset of UPR effectors. During ER stress, IGF2BP3 destabilized many of these target transcripts, including UPR targets. In contrast, IGF2BP3 stabilized mRNAs encoding transcriptional regulators and thereby upregulated expression of UPR target genes. This dual regulation allows IGF2BP3 to differentially upregulate stress response genes while tuning down the expression of other transcripts during ER stress, relieving protein folding load during this critical response. Our data reveal that posttranscriptional mechanisms control transcription, thus forming gene regulatory networks that robustly tune the UPR.
