Abstract
Sphingolipids are not only important components of membranes but also have functions in protein trafficking and intracellular signaling. The LCB1 gene encodes a subunit of the serine palmitoyltransferase, which is responsible for the first step of sphingolipid synthesis. Here, we show that activation of the unfolded protein response (UPR) can restore normal ceramide levels and viability in yeast cells with a conditional defect in LCB1. Dependence on UPR was demonstrated by showing the HAC1-dependence of the suppression. A similar induction of ceramides by UPR seems to take place in mammalian cells. In rat pancreatic INS-1E cells, UPR activation induces the transcription of the CerS6 gene, which encodes a ceramide synthase. This correlates with the specific accumulation of ceramide with a C16 fatty acyl chain upon UPR activation. Therefore, our study reveals a novel connection between UPR induction and ceramide synthesis that seems to be conserved between yeast and mammalian cells.
Highlights
Sphingolipids are important components of membranes and have functions in protein trafficking and intracellular signaling
The major finding of this study was that ceramide levels are substantially increased upon induction of the unfolded protein response (UPR) pathway in both yeast and pancreatic INS-1E cells
The initial discovery of the increase in ceramide synthesis came from studies of a specific double mutant defective in serine palmitoyltransferase (SPT) and the p24 family member, Emp24p, which is required for GPI-anchored protein exit from the endoplasmic reticulum (ER) and induces the UPR pathway when absent
Summary
Sphingolipids are important components of membranes and have functions in protein trafficking and intracellular signaling. The LCB1 gene encodes a subunit of the serine palmitoyltransferase, which is responsible for the first step of sphingolipid synthesis. We show that activation of the unfolded protein response (UPR) can restore normal ceramide levels and viability in yeast cells with a conditional defect in LCB1. It was shown that the lcb100 mutant is defective in the same transport step [17] Another set of proteins that are required for the transport of GPI-anchored proteins to the Golgi in yeast and mammalian cells is the p24 family [20,21,22,23]. Mutations of members of the p24 complex in Abbreviations: ER, endoplasmic reticulum; GPI, glycosylphosphosphatidylinositol; IPC, inositolphosphorylceramide; PHC, phytoceramide; SPT, serine palmitoyltransferase; UPR, unfolded protein response
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