Membrane lipids and the endoplasmic reticulum unfolded protein response: An interesting relationship

摘要

The unfolded protein response of the endoplasmic reticulum (UPR^ER) is a conserved signaling circuit that ensures ER protein homeostasis (proteostasis). In the UPR^ER of higher eukaryotes, multiple sensors cooperatively perceive proteostatic disturbances in the ER lumen and induce downstream adaptive changes. Besides direct proteotoxic insults, altered lipid profiles can also lead to UPR^ER activation, evidently because abnormal lipid composition impairs protein folding. However, 2 recent studies propose an alternative mechanism of UPR^ER sensor activation. In one report, UPR^ER activation occurred in cells expressing UPR^ER sensors lacking the very domains that sense unfolded proteins; the other study found that Caenorhabditis elegans worms displayed UPR^ER activation without apparent proteostatic imbalance in the ER lumen. Collectively, these studies suggest that lipid disequilibrium-activated UPR^ER is not strictly accompanied by compromised ER proteostasis and hint at a lipid membrane-monitoring role of the UPR^ER. These discoveries raise several important questions: does the UPR^ER monitor and maintain homeostasis of the ER membrane and/or its lipids? In turn, does the UPR^ER initiate downstream regulatory events that specifically alleviate lipid or proteostatic imbalance? And what is the physiological significance of proteostasis-independent UPR^ER activation? In this commentary, we will discuss these issues and highlight the utility of C. elegans as an in vivo model to study lipid disequilibrium-induced UPR^ER and related pathways.