Ubiquitin-dependent signal amplification in lipid saturation sensing

Cellular membranes are dynamic platforms whose composition and biophysical properties are surveyed by sensor proteins to maintain homeostasis. Failure to preserve membrane homeostasis, however, results in cellular stress and organelle dysfunction. Using the prototypical lipid saturation sensor Mga2, we explored how weak physical cues that modulate rotational movements in the transmembrane region are converted into decisive biochemical outputs that ultimately control the production of unsaturated fatty acids. Quantitative in vitro ubiquitylation assays and kinetic modeling reveal vastly distinct rates of Mga2 ubiquitylation controlled by the membrane environment. Mga2 ubiquitylation dominates in tightly packed, saturated membranes, while loosely packed environments favor an inhibitory autoubiquitylation of the cognate E3 ligase Rsp5. This mechanism provides a means of signal amplification, which can function even in the absence of deubiquitylating enzymes. Our findings provide a mechanistic framework for how membrane property sensors convert weak, fluctuating physical cues into robust biochemical outcomes, and put a spotlight on the regulatory potential of E3 ligase autoubiquitylation in cellular surveillance.