Membrane homeostasis beyond fluidity: control of membrane compressibility.

The lipidome of cells and organelles is more complex than originally anticipated. It has become clear that biomembranes are active materials bearing a tremendous regulatory potential. Cells control the collective biophysical properties of their organelle membranes in order to maintain the organization and functionality of the membrane proteome. The concept of homeoviscous adaptation provided an intuitive interpretation for the changes of membrane compositions with temperature. However, the mechanistic relevance of membrane viscosity for many cellular processes including those regulating the lipid fatty acyl chain composition has been recently challenged. The crucial role of membrane compressibility and thickness in organizing the membrane proteome, however, has gained fresh emphasis. The transverse membrane compressibility of the endoplasmic reticulum (ER) membrane modulates crucial aspects of transmembrane protein biology including their bilayer insertion and extraction, their conformational dynamics and activity, as well as their sorting along the secretory pathway and inheritance from mother to daughter cells. The unfolded protein response (UPR) can sense aberrant ER membrane stiffening and surfaces as a prime candidate for balancing membrane lipid and protein production at the ER as a mechanism of biophysical membrane homeostasis during cellular stress. Biomembranes are complex materials composed of lipids and proteins that compartmentalize biochemistry. They are actively remodeled in response to physical and metabolic cues, as well as during cell differentiation and stress. The concept of homeoviscous adaptation has become a textbook example of membrane responsiveness. Here, we discuss limitations and common misconceptions revolving around it. By highlighting key moments in the life cycle of a transmembrane protein, we illustrate that membrane thickness and a finely regulated membrane compressibility are crucial to facilitate proper membrane protein insertion, function, sorting, and inheritance. We propose that the unfolded protein response (UPR) provides a mechanism for endoplasmic reticulum (ER) membrane homeostasis by sensing aberrant transverse membrane stiffening and triggering adaptive responses that re-establish membrane compressibility. [ABSTRACT FROM AUTHOR]