ABSTRACT
Background Phospholipid homeostasis in biological membranes is essential to maintain functions of organelles such as the endoplasmic reticulum. Phospholipid perturbation has been associated to non-alcoholic fatty liver disease, obesity and other metabolic disorders. However, in most cases, the biological significance of lipid disequilibrium remains unclear. Previously, we reported that Saccharomyces cerevisiae adapts to lipid disequilibrium by upregulating several protein quality control pathways such as the endoplasmic reticulum-associated degradation (ERAD) pathway and the unfolded protein response (UPR).
Results Surprisingly, we observed certain ER-resident transmembrane proteins (TPs), which form part of the UPR programme, to be destabilised under lipid perturbation (LP). Among these, Sbh1 was prematurely degraded by fatty acid remodelling and membrane stiffening of the ER. Moreover, the protein translocon subunit Sbh1 is targeted for degradation through its transmembrane domain in an unconventional Doa10-dependent manner.
Conclusion Premature removal of key ER-resident TPs might be an underlying cause of chronic ER stress in metabolic disorders.
LIST OF ABBREVIATIONS
- co-IP
- co-immunoprecipitation
- CytoQC
- cytosolic protein quality control
- DMPE
- N-dimethyl phosphatidylethanolamine
- ER
- endoplasmic reticulum
- ERAD
- endoplasmic reticulum-associated degradation
- FA
- fatty acid
- LP
- lipid perturbation
- MMPE
- N-monomethyl phosphatidylethanolamine
- MYTH
- membrane yeast two hybrid
- NAFLD
- non-alcoholic fatty liver disease
- NASH
- non-alcoholic steatohepatitis
- PC
- phosphatidylcholine
- PE
- phosphatidylethanolamine
- SERCA
- sarco/endoplasmic reticulum Ca2+-ATPase
- T2D
- type II diabetes
- TP
- transmembrane protein
- UPR
- unfolded protein response
