Regulation of lipid saturation without sensing membrane fluidity.

Cells maintain membrane fluidity by regulating lipid saturation, but the molecular mechanisms of this homeoviscous adaptation remain poorly understood. We have reconstituted the core machinery for regulating lipid saturation in baker's yeast to study its molecular mechanism. By combining molecular dynamics simulations with experiments, we uncover a remarkable sensitivity of the transcriptional regulator Mga2 to the abundance, position, and configuration of double bonds in lipid acyl chains, and provide insights into the molecular rules of membrane adaptation. Our data challenge the prevailing hypothesis that membrane fluidity serves as the measured variable for regulating lipid saturation. Rather, we show that Mga2 senses the molecular lipid-packing density in a defined region of the membrane. Our findings suggest that membrane property sensors have evolved remarkable sensitivities to highly specific aspects of membrane structure and dynamics, thus paving the way toward the development of genetically encoded reporters for such properties in the future.

Cellular mechanisms of physicochemical membrane homeostasis.

Biological membranes are vital, active contributors to cell function. In addition to specific interactions of individual lipid molecules and lateral organization produced by membrane domains, the bulk physicochemical properties of biological membranes broadly regulate protein structure and function. Therefore, these properties must be homeostatically maintained within a narrow range that is compatible with cellular physiology. Although such adaptiveness has been known for decades, recent observations have dramatically expanded its scope by showing the breadth of membrane properties that must be maintained, and revealing the remarkable diversity of biological membranes, both within and between cell types. Cells have developed a broad palette of sense-and-respond machineries to mediate physicochemical membrane homeostasis, and the molecular mechanisms of these are being discovered through combinations of cell biology, biophysical approaches, and computational modeling.

An Emerging Group of Membrane Property Sensors Controls the Physical State of Organellar Membranes to Maintain Their Identity.

The biological membranes of eukaryotic cells harbor sensitive surveillance systems to establish, sense, and maintain characteristic physicochemical properties that ultimately define organelle identity. They are fundamentally important for membrane homeostasis and play active roles in cellular signaling, protein sorting, and the formation of vesicular carriers. Here, we compare the molecular mechanisms of Mga2 and Ire1, two sensors involved in the regulation of fatty acid desaturation and the response to unfolded proteins and lipid bilayer stress in order to identify their commonalities and specializations. We will speculate on the cellular significance of membrane property sensors in other organelles and discuss their putative mechanisms. Based on these findings, we propose membrane property sensors as an emerging class of proteins with wide implications for organelle communication and function.

Control of membrane fluidity: the OLE pathway in focus.

The maintenance of a fluid lipid bilayer is key for membrane integrity and cell viability. We are only beginning to understand how eukaryotic cells sense and maintain the characteristic lipid compositions and bulk membrane properties of their organelles. One of the key factors determining membrane fluidity and phase behavior is the proportion of saturated and unsaturated acyl chains in membrane lipids. Saccharomyces cerevisiae is an ideal model organism to study the regulation of the lipid acyl chain composition via the OLE pathway. The OLE pathway comprises all steps involved in the regulated mobilization of the transcription factors Mga2 and Spt23 from the endoplasmic reticulum (ER), which then drive the expression of OLE1 in the nucleus. OLE1 encodes for the essential Δ9-fatty acid desaturase Ole1 and is crucial for de novo biosynthesis of unsaturated fatty acids (UFAs) that are used as lipid building blocks. This review summarizes our current knowledge of the OLE pathway, the best-characterized, eukaryotic sense-and-control system regulating membrane lipid saturation, and identifies open questions to indicate future directions.

A Eukaryotic Sensor for Membrane Lipid Saturation.

Maintaining a fluid bilayer is essential for cell signaling and survival. Lipid saturation is a key factor determining lipid packing and membrane fluidity, and it must be tightly controlled to guarantee organelle function and identity. A dedicated eukaryotic mechanism of lipid saturation sensing, however, remains elusive. Here we show that Mga2, a transcription factor conserved among fungi, acts as a lipid-packing sensor in the ER membrane to control the production of unsaturated fatty acids. Systematic mutagenesis, molecular dynamics simulations, and electron paramagnetic resonance spectroscopy identify a pivotal role of the oligomeric transmembrane helix (TMH) of Mga2 for intra-membrane sensing, and they show that the lipid environment controls the proteolytic activation of Mga2 by stabilizing alternative rotational orientations of the TMH region. This work establishes a eukaryotic strategy of lipid saturation sensing that differs significantly from the analogous bacterial mechanism relying on hydrophobic thickness.