ATF6 shapes PERK and IRE1 signaling dynamics during ER stress

Abstract The Unfolded Protein Response (UPR) is a conserved network of signaling pathways controlled by the Endoplasmic Reticulum (ER) anchored stress sensors IRE1, PERK and ATF6. The UPR’s primary function is to help cells manage and resolve ER stress. Compared with the well-characterized IRE1 and PERK pathways, how ATF6 shapes the wider UPR network is still largely unresolved. Using pharmacological inhibition, genetic knockout, and inducible expression models, we show that ATF6 signaling intersects with both the PERK and IRE1 branches of the UPR. During early ER stress, ATF6 promotes PERK expression, with inhibition or loss of ATF6 lowering PERK levels, while selective induction of active ATF6 drives PERK upregulation. As stress shifts from acute to prolonged exposure, ATF6 signaling helps to dampen IRE1 RNase activity. Cells lacking ATF6 or treated with ATF6 inhibitors exhibit prolonged IRE1 RNase activity, while induction of active ATF6 suppresses IRE1 signaling. Our findings identify an unappreciated role for ATF6 as a temporal modulator of UPR signaling, underscoring the importance of communication between ER stress sensors in fine-tuning adaptive responses that dictate cellular outcomes during ER stress.