RT Journal Article
SR Electronic
T1 Lipid Biosynthesis Perturbation Impairs Endoplasmic Reticulum-Associated Degradation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.12.09.519544
DO 10.1101/2022.12.09.519544
A1 Samantha M. Turk
A1 Christopher J. Indovina
A1 Danielle L. Overton
A1 Avery M. Runnebohm
A1 Cade J. Orchard
A1 Ellen M. Doss
A1 Kyle A. Richards
A1 Courtney Broshar Irelan
A1 Mahmoud M. Daraghmi
A1 Connor G. Bailey
A1 Jacob M. Miller
A1 Julia M. Niekamp
A1 Samantha K. Gosser
A1 Mary E. Tragesser-Tiña
A1 Kieran P. Claypool
A1 Sarah M. Engle
A1 Bryce W. Buchanan
A1 Kelsey A. Woodruff
A1 James B. Olesen
A1 Philip J. Smaldino
A1 Eric M. Rubenstein
YR 2022
UL http://biorxiv.org/content/early/2022/12/10/2022.12.09.519544.abstract
AB The relationship between lipid homeostasis and protein homeostasis (proteostasis) is complex and remains incompletely understood. We conducted a screen for genes required for efficient degradation of Deg1-Sec62, a model aberrant translocon-associated substrate of the endoplasmic reticulum (ER) ubiquitin ligase Hrd1, in Saccharomyces cerevisiae. This screen revealed that INO4 is required for efficient Deg1-Sec62 degradation. INO4 encodes one subunit of the Ino2/Ino4 heterodimeric transcription factor, which regulates expression of genes required for lipid biosynthesis. Deg1-Sec62 degradation was also impaired by mutation of genes encoding several enzymes mediating phospholipid and sterol biosynthesis. The degradation defect in ino4Δ yeast was rescued by supplementation with metabolites whose synthesis and uptake are mediated by Ino2/Ino4 targets. Stabilization of a panel of substrates of the Hrd1 and Doa10 ER ubiquitin ligases by INO4 deletion indicates ER protein quality control is generally sensitive to perturbed lipid homeostasis. Further, loss of INO4 sensitized yeast to proteotoxic stress, suggesting a broad requirement for lipid homeostasis in maintaining proteostasis. Abundance of the ER ubiquitin-conjugating enzyme Ubc7 was reduced in the absence of INO4, consistent with a model whereby perturbed lipid biosynthesis alters the abundance of critical protein quality control mediators, with broad consequences for ER proteostasis. A better understanding of the dynamic relationship between lipid homeostasis and proteostasis may lead to improved understanding and treatment of several human diseases associated with altered lipid biosynthesis.Competing Interest StatementThe authors have declared no competing interest.