Adaptation of eukaryotic membrane homeostasis to species-specific cellular lipid landscapes

Abstract The physicochemical properties of biological membranes must be maintained within a range compatible with cellular physiology. In the face of external perturbations, membrane lipid homeostasis mechanisms sense and control membrane features. How such mechanisms evolve to function in organisms with different cellular lipid make-up is unknown. Here, we address this fundamental question by exploiting the natural divergence in membrane lipid composition between the related fission yeasts S. pombe and S. japonicus . Using lipidomics and transcriptomics, we show that the activity of the membrane-bound transcriptional activator Mga2, which regulates the Δ-9 desaturase Ole1 expression, is set to sense distinct levels of membrane unsaturation in the two species. Through retro-engineering and physiological experiments, we identify an evolutionary divergent but functionally constrained element within the juxtamembrane region of Mga2, which fine-tunes its performance to species-specific lipid composition. Our experiments indicate that high baseline expression of ole1 , set by cis-regulatory elements in its upstream non-coding region, has redefined the dynamic range of Mga2 activation in S. pombe , supporting high lipidome unsaturation. Our work explores an “experiment of nature” to highlight the broad principles underlying the organisation and evolution of membrane homeostasis, which should be applicable to other genetic networks supporting cellular homeostatic processes.