TORC1 inhibits GSK3-mediated Elo2 phosphorylation to regulate very long chain fatty acid synthesis and autophagy.
Very long chain fatty acids (VLCFAs) are essential fatty acids with multiple functions, including ceramide synthesis. Although the components of the VLCFA biosynthetic machinery have been elucidated, how their activity is regulated to meet the cell's metabolic demand remains unknown. The goal of this study was to identify mechanisms that regulate the rate of VLCFA synthesis, and we discovered that the fatty acid elongase Elo2 is regulated by phosphorylation. Elo2 phosphorylation is induced upon inhibition of TORC1 and requires GSK3. Expression of nonphosphorylatable Elo2 profoundly alters the ceramide spectrum, reflecting aberrant VLCFA synthesis. Furthermore, VLCFA depletion results in constitutive activation of autophagy, which requires sphingoid base phosphorylation. This constitutive activation of autophagy diminishes cell survival, indicating that VLCFAs serve to dampen the amplitude of autophagy. Together, our data reveal a function for TORC1 and GSK3 in the regulation of VLCFA synthesis that has important implications for autophagy and cell homeostasis.
Department of Microbiology, Oslo University Hospital, and University of Oslo, 0027 Oslo, Norway.
Christine
C
Zimmermann
Aline
A
Santos
Kenneth
K
Gable
Sharon
S
Epstein
Charulatha
C
Gururaj
Pierre
P
Chymkowitch
Dennis
D
Pultz
Steven V
SV
Rødkær
Lorena
L
Clay
Magnar
M
Bjørås
Yves
Y
Barral
Amy
A
Chang
Nils J
NJ
Færgeman
Teresa M
TM
Dunn
Howard
H
Riezman
Jorrit M
JM
Enserink
D000123:Acetyltransferases / Q000096:biosynthesis / Q000378:metabolism*; D001343:Autophagy; D002470:Cell Survival; D002518:Ceramides / Q000096:biosynthesis; D005228:Fatty Acids, Essential / Q000096:biosynthesis*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000378:metabolism*; D010766:Phosphorylation; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*
D002518:Ceramides; D005228:Fatty Acids, Essential; D008565:Membrane Proteins; D029701:Saccharomyces cerevisiae Proteins; C561842:TORC1 protein complex, S cerevisiae; D014157:Transcription Factors; D000123:Acetyltransferases; C107118:ELO2 protein, S cerevisiae; D038362:Glycogen Synthase Kinase 3; C068124:MCK1 protein, S cerevisiae