Activation of the unfolded protein response pathway causes ceramide accumulation in yeast and INS-1E insulinoma cells.
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.
Department of Biochemistry, University of Geneva, Geneva, Switzerland.
Sharon
S
Epstein
Department of Cell Physiology and Metabolism, Centre Médical Universitaire, University of Geneva, Geneva, Switzerland.
Clare L
CL
Kirkpatrick
Department of Biochemistry, University of Geneva, Geneva, Switzerland.
Guillaume A
GA
Castillon
Department of Cell Biology, University of Sevilla, Seville, Spain Lausanne, Switzerland.
Manuel
M
Muñiz
Department of Biochemistry, University of Geneva, Geneva, Switzerland.
Isabelle
I
Riezman
Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Fabrice P A
FPA
David
Department of Cell Physiology and Metabolism, Centre Médical Universitaire, University of Geneva, Geneva, Switzerland.
Claes B
CB
Wollheim
Department of Biochemistry, University of Geneva, Geneva, Switzerland. Electronic address: howard.riezman@unige.ch.
Howard
H
Riezman
D000818:Animals; D045744:Cell Line, Tumor; D002518:Ceramides / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000235:genetics / Q000502:physiology; D007340:Insulinoma / Q000378:metabolism*; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D013109:Sphingomyelins / Q000378:metabolism; D056811:Unfolded Protein Response / Q000235:genetics / Q000502:physiology*; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism
D002518:Ceramides; C093262:EMP24 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D013109:Sphingomyelins; D033921:Vesicular Transport Proteins; C097760:N-palmitoylsphingosine; D010088:Oxidoreductases; C473786:dihydroceramide synthase