Broad Roles of Endoplasmic Reticulum Stress Sensors Activated by Diverse Pathophysiological Stimuli

The endoplasmic reticulum (ER) stress response is a critical cellular program that maintains proteostasis and membrane homeostasis through the activation of the ER stress sensor proteins inositol-requiring enzyme 1 (IRE1), protein kinase R-like ER kinase (PERK), activating transcription factor 6 (ATF6), and old astrocyte specifically induced substance (OASIS) family proteins. These sensors, canonically understood as transducers of the unfolded protein response (UPR), respond to the accumulation of misfolded proteins in the ER lumen as a result of ER luminal Ca²⁺ depletion, defective disulfide bond formation, dysregulated glycosylation, or inhibition of ER-associated degradation. However, recent conceptual advances have reshaped understanding of these classical mechanisms, by revealing multiple non-canonical pathways that operate independently of luminal proteotoxicity. Emerging evidence highlights the roles of ER stress sensors in integrating diverse stimuli, including the integrated stress response, lipid bilayer stress, mitochondria-ER contact, and the DNA damage response. Herein, we discuss how these ER stress sensors function as multidimensional signaling hubs for proteotoxic, metabolic, and genomic stresses, and consequently modulate pathophysiological cellular outcomes. Finally, we examine current knowledge regarding both canonical and non-canonical modes of ER stress sensor activation, and we discuss how these mechanisms expand the functional scope of ER stress signaling in physiological regulation and diseases.