The unfolded protein response (UPR) is sensitive to both proteotoxic stress and membrane bilayer stress. These stresses are sensed by the ER transmembrane protein Ire1. When activated, Ire1 uses its endonuclease activity to splice HAC1mRNA, producing a mature transcription factor that binds to UPR elements (UPREs) in the promoters of target genes. Hac1 targets include not only genes involved in protein folding, secretion, and degradation, but also a subset of lipid metabolic genes. One aspect of lipid metabolism is the deacylation of phosphatidylcholine (PC) by phospholipases to produce glycerophosphocholine (GPC). In Saccharomyces cerevisiae, GPC can be reacylated in a novel two-step process catalyzed first by GPC acyltransferase Gpc1, followed by acylation of the lyso-PC molecule by Ale1. This metabolic cycle has been termed the PC deacylation/reacylation pathway (PC-DRP). In prior studies, loss of Gpc1 was shown to result in an increase in di-unsaturated PC species at the expense of mono-unsaturated PC species, indicating a role for PC-DRP in PC acyl chain remodeling. Here, we probe the role of Gpc1 as both a target and an effector of the UPR. Exposure to the UPR-inducing compounds tunicamycin, DTT, and canavanine results in an increase in GPC1 message that is dependent upon the UPR transcriptional activator Hac1. The importance of this increased expression to cellular function is illustrated by the finding that cells lacking Gpc1 exhibit increased sensitivity to those compounds. In a converse set of experiments, we show that that loss of GPC1 results in upregulation of the UPR as measured by expression of the ER chaperone KAR2. Consistent with these findings, we show that Gpc1 primarily co-localizes with the endoplasmic reticulum.

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Journal Article

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Hrach VL, Nelson L, King W, Conklin S, Patton-Vogt J

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