From the unfolded protein response to metabolic diseases – lipids under the spotlight

Abstract

The unfolded protein response (UPR) is classically viewed as a stress response pathway to maintain protein homeostasis at the endoplasmic reticulum (ER). However, it has recently emerged that the UPR can be directly activated by lipid perturbation, independently of misfolded proteins. Comprising primarily phospholipids, sphingolipids and sterols, individual membranes can contain hundreds of distinct lipids. Even with such complexity, lipid distribution in a cell is tightly regulated by mechanisms that remain incompletely understood. It is therefore unsurprising that lipid dysregulation can be a key factor in disease development. Recent advances in analysis of lipids and their regulators have revealed remarkable mechanisms and connections to other cellular pathways including the UPR. In this Review, we summarize the current understanding in UPR transducers functioning as lipid sensors and the interplay between lipid metabolism and ER homeostasis in the context of metabolic diseases. We attempt to provide a framework consisting of a few key principles to integrate the different lines of evidence and explain this rather complicated mechanism.

ER stress sensor Ire1 deploys a divergent transcriptional program in response to lipid bilayer stress

“…Conical PE and cylindrical PC promote negative and minimal membrane curvature, respectively [7,67,68]. The phospholipid intermediate N-monomethyl phosphatidylethanolamine (MMPE), generated during de novo synthesis of PC from PE, exhibits physical properties similar to PE which becomes highly abundant under the ablation of OPI3 [23,24].…”

“…During periods of environmental stress [4], disease, infection or aging [5,6], ERQC is compromised, leading to the accumulation of misfolded proteins and causes ER stress. In turn, ER stress activates the evolutionarily conserved unfolded protein response (UPR) to restore ER homeostasis; if unresolved, chronic ER stress leads to apoptosis (for a review, see [7]). In metazoans, the three transmembrane protein transducers inositol requiring enzyme 1 (Ire1), protein kinase RNA (PKR)-like ER kinase (PERK) and activating transcription factor 6 (ATF6) sense ER stress and activate downstream cascades as part of the UPR program.…”

Cysteine crosslinking in native membranes establishes the transmembrane architecture of Ire1

“…Lipid bilayer stress due to aberrant compositions of the ER membrane is equally potent in activating the UPR (19–21). This membrane-based mechanism is conserved throughout evolution (20, 22, 23) and has been implicated in the lipotoxicity associated with obesity and type II diabetes (4, 24). We have shown that Ire1 from baker’s yeast inserts an amphipathic helix (AH) into the luminal leaflet of the ER-membrane, thereby forcing the adjacent TMH in a tilted configuration that locally squeezes the bilayer (25).…”

Glucose increases the lifespan of post-reproductiveC. elegansindependently of FOXO

“…Prominent metabolic diseases, namely type 2 diabetes and insulin resistance, have a strong association with endoplasmic reticulum (ER) stress 2 . Upon ER stress, the unfolded protein response (UPR) is activated to limit cellular damage by adapting to stress conditions and restoring ER homeostasis 3,4 . However, adaptive genes upregulated from the UPR tend to decrease with age 5 .…”