A Eukaryotic Sensor for Membrane Lipid Saturation

Abstract

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.

Control of membrane fluidity: the OLE pathway in focus

“…However, prolonged periods of hypoxia do affect the membrane lipid composition of the ER and force the cells to react. The membrane-sensitive Mga2 is key to mount an adaptive response by sensing the shortage of ergosterol and unsaturated lipid in the ER-membrane and activating the expression of ERG1 and OLE1 (Zhang et al, 1999;Rice et al, 2010;Covino et al, 2016). In this light, the ER-membrane serves as 'memory device' to integrate a long-term signal for oxygen availability, which is encoded by the lipid composition (Covino et al, 2016;Ernst et al, 2016).…”

“…The membrane-sensitive Mga2 is key to mount an adaptive response by sensing the shortage of ergosterol and unsaturated lipid in the ER-membrane and activating the expression of ERG1 and OLE1 (Zhang et al, 1999;Rice et al, 2010;Covino et al, 2016). In this light, the ER-membrane serves as 'memory device' to integrate a long-term signal for oxygen availability, which is encoded by the lipid composition (Covino et al, 2016;Ernst et al, 2016). This elegant mechanism of signal integration is apparently conserved among fungi, as the homolog of Mga2 in S. pombe was recently identified as oxygen-responsive modulator of lipid homeostasis (Burr et al, 2016).…”

“…Based on these findings, a causal relationship between OLE1 repression and the melting point of these UFAs had been suggested (Fujiwara et al, 1998). The observation that Spt23 and Mga2 exist as homodimeric, membrane-embedded precursors (Hoppe et al, 2000;Rape et al, 2001;Shcherbik and Haines, 2007), and that their proteolytic processing is controlled by dietary UFAs (Hoppe et al, 2000;Covino et al, 2016) paved the way toward the identification of the underlying molecular mechanism of regulation. Using a multi-disciplinary pipeline to study intra-membrane processes, we could show that Mga2 uses its transmembrane helix (TMH) to sense the proportion of unsaturated lipids in the ER-membrane (Covino et al, 2016) (Figure 2).…”

“…The overproduction of unsaturated lipids, however, is equally harmful and can cause fatty acid-induced necrosis (Richly et al, 2005;Rockenfeller et al, 2010;Hapala et al, 2011;Eisenberg and Buettner, 2014;Ruggles et al, 2014). The best-characterized eukaryotic surveillance system of lipid saturation is the OLE pathway (Covino et al, 2016;Ernst et al, 2016). Intriguingly, the eukaryotic and prokaryotic sensing mechanisms differ significantly and have recently been compared and discussed .…”

“…system (UPS) by Stefan Jentsch and colleagues relied on the dramatic phenotypes associated with a deregulated UFA production in S. cerevisiae (Hoppe et al, 2000;Rape et al, 2001;Richly et al, 2005;Rumpf and Jentsch, 2006;Siepe and Jentsch, 2009). We could recently show that the homodimeric transcription factor Mga2 acts as a membrane sensor, whose conformation is controlled by the membrane environment (Covino et al, 2016) (Figure 2). The molecular lipid packing density in the core of the membrane determines the conformation in the transmembrane region, which ultimately controls the ubiquitylation, proteolytic processing and mobilization of the transcriptionally active p90 (Figure 2).…”