Abstract
Phospholipid homeostasis in biological membranes is essential to maintain functions of organelles such as the endoplasmic reticulum. Phospholipid perturbation has been associated to cellular stress responses. However, in most cases, the implication of membrane lipid changes to homeostatic cellular response has not been clearly defined. Previously, we reported that Saccharomyces cerevisiae adapts to lipid bilayer stress by upregulating several protein quality control pathways such as the endoplasmic reticulum-associated degradation (ERAD) pathway and the unfolded protein response (UPR). Surprisingly, we observed certain ER-resident transmembrane proteins, which form part of the UPR programme, to be destabilised under lipid bilayer stress. Among these, the protein translocon subunit Sbh1 was prematurely degraded by membrane stiffening at the ER. Moreover, our findings suggest that the Doa10 complex recognises free Sbh1 that becomes increasingly accessible during lipid bilayer stress, perhaps due to the change in ER membrane properties. Premature removal of key ER-resident transmembrane proteins might be an underlying cause of chronic ER stress as a result of lipid bilayer stress.
Highlights
Phospholipid homeostasis is crucial in the maintenance of various cellular processes and functions
To exclude possible cellular functions that could be grossly affected from lipid bilayer stress such as transport and secretion, we focused on the endoplasmic reticulum (ER)-resident proteins Cue[1], Emc[4], Nsg[2], and Sbh[1]
We demonstrated that some of these proteins are in low abundance while other components of their respective complexes are successfully upregulated by the unfolded protein response (UPR) upon lipid bilayer stress, suggesting the premature degradation of proteins that are normally upregulated by the UPR14
Summary
Phospholipid homeostasis is crucial in the maintenance of various cellular processes and functions. As PC and PE form the bulk of biological membranes, the perturbation of PC and PE levels results in lipid bilayer stress, which in turn causes endoplasmic reticulum (ER) stress[8,9]. Phospholipid perturbation was shown to cause the premature degradation of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) ion pump, disrupting calcium homeostasis and resulting in chronic ER stress[10]. This eventually led to hepatic steatosis and liver failure. We developed a lipid bilayer stress yeast model to recapitulate a major contributor to NAFLD pathophysiology by deleting the gene OPI314. Through a general attenuation of protein translation, together with the enhanced clearance of misfolded proteins and protein folding capacity[18], the UPR aims to achieve ER homeostasis
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