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

Abstract

The unfolded protein response of the endoplasmic reticulum (UPRER) is a conserved signaling circuit that ensures ER protein homeostasis (proteostasis). In the UPRER 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 UPRER activation, evidently because abnormal lipid composition impairs protein folding. However, 2 recent studies propose an alternative mechanism of UPRER sensor activation. In one report, UPRER activation occurred in cells expressing UPRER sensors lacking the very domains that sense unfolded proteins; the other study found that Caenorhabditis elegans worms displayed UPRER activation without apparent proteostatic imbalance in the ER lumen. Collectively, these studies suggest that lipid disequilibrium-activated UPRER is not strictly accompanied by compromised ER proteostasis and hint at a lipid membrane-monitoring role of the UPRER. These discoveries raise several important questions: does the UPRER monitor and maintain homeostasis of the ER membrane and/or its lipids? In turn, does the UPRER initiate downstream regulatory events that specifically alleviate lipid or proteostatic imbalance? And what is the physiological significance of proteostasis-independent UPRER 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 UPRER and related pathways.