The Membrane Stress Response Buffers Lethal Effects of Lipid Disequilibrium by Reprogramming the Protein Homeostasis Network

Lipid composition can differ widely among organelles and even between leaflets of a membrane. Lipid homeostasis is critical because disequilibrium can have disease outcomes. Despite their importance, mechanisms maintaining lipid homeostasis remain poorly understood. Here, we establish a model system to study the global effects of lipid imbalance. Quantitative lipid profiling was integral to monitor changes to lipid composition and for system validation. Applying global transcriptional and proteomic analyses, a dramatically altered biochemical landscape was revealed from adaptive cells. The resulting composite regulation we term the “membrane stress response” (MSR) confers compensation, not through restoration of lipid composition, but by remodeling the protein homeostasis network. To validate its physiological significance, we analyzed the unfolded protein response (UPR), one facet of the MSR and a key regulator of protein homeostasis. We demonstrate that the UPR maintains protein biogenesis, quality control, and membrane integrity—functions otherwise lethally compromised in lipid dysregulated cells. [Display omitted] ► Membrane lipid imbalance activates the membrane stress response ► The MSR broadly reprograms the protein homeostasis network ► The MSR buffers the lethal effects of lipid disequilibrium ► The UPR arm maintains membrane functionality without remodeling lipid composition