RT Journal Article
SR Electronic
T1 A subset of UPR-induced transmembrane proteins are prematurely degraded during lipid perturbation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 178947
DO 10.1101/178947
A1 Ng, Benjamin S.H.
A1 Shyu, Peter
A1 Ho, Nurulain
A1 Chaw, Ruijie
A1 Ling, Seah Yi
A1 Thibault, Guillaume
YR 2018
UL http://biorxiv.org/content/early/2018/06/11/178947.abstract
AB 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.co-IPco-immunoprecipitationCytoQCcytosolic protein quality controlDMPEN-dimethyl phosphatidylethanolamineERendoplasmic reticulumERADendoplasmic reticulum-associated degradationFAfatty acidLPlipid perturbationMMPEN-monomethyl phosphatidylethanolamineMYTHmembrane yeast two hybridNAFLDnon-alcoholic fatty liver diseaseNASHnon-alcoholic steatohepatitisPCphosphatidylcholinePEphosphatidylethanolamineSERCAsarco/endoplasmic reticulum Ca2+-ATPaseT2Dtype II diabetesTPtransmembrane proteinUPRunfolded protein response