1 Faculty of Science, SDU2 Department of Biochemistry and Molecular Biology, Faculty of Science, SDU3 Syddansk Universitet4 Department of Biochemistry and Molecular Biology, Faculty of Science, SDU
Eukaryotic cells have developed several strategies to respond and adapt to changes in their intracellular and extracellular environment. The unfolded protein response (UPR) pathway is activated following accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER), whereas autophagy mainly is a response to the stress of nutrient limitation. In the present study, we demonstrate that perturbation of fatty acid synthesis and transport either through inhibition of fatty acid synthase (FAS) or by depleting cells for the acyl-CoA binding protein, Acb1p, leads to induction of Hac1p, a transcription factor regulating the unfolded protein response and membrane biogenesis, as well as Hac1p target genes incl. KAR2 and PDI1. Under similar conditions, we find a massive upregulation of pre-autophagosomal structure (PAS) formation, indicative of upregulation of autophagy. Supplementation with exogenous fatty acids suppresses induction of both the UPR pathway and autophagy in cells lacking Acb1p. Activation of the Ras-cAMP signalling pathway by overexpressing TPK1 or the RAS1val19 allele in Acb1p-depleted cells reduced the number of pre-autophagosomal structures to wild type levels. This and the facts that Acb1p-depleted cells are hypersensitive to the immunosuppressive drug rapamycin and accumulate the transcription factor Msn2p in the nucleus, indicate that perturbation of intracellular acyl-CoA metabolism leads to a starvation response that upregulate autophagy, which involves both Ras-cAMP and TOR1 signalling.
Chemistry and Physics of Lipids, 2008, Vol 154, Issue s1