Regulation of Gene Expression through a Transcriptional Repressor that Senses Acyl-Chain Length in Membrane Phospholipids

Summary

Membrane phospholipids typically contain fatty acids (FAs) of 16 and 18 carbon atoms. This particular chain length is evolutionarily highly conserved and presumably provides maximum stability and dynamic properties to biological membranes in response to nutritional or environmental cues. Here, we show that the relative proportion of C16 versus C18 FAs is regulated by the activity of acetyl-CoA carboxylase (Acc1), the first and rate-limiting enzyme of FA de novo synthesis. Acc1 activity is attenuated by AMPK/Snf1-dependent phosphorylation, which is required to maintain an appropriate acyl-chain length distribution. Moreover, we find that the transcriptional repressor Opi1 preferentially binds to C16 over C18 phosphatidic acid (PA) species: thus, C16-chain containing PA sequesters Opi1 more effectively to the ER, enabling AMPK/Snf1 control of PA acyl-chain length to determine the degree of derepression of Opi1 target genes. These findings reveal an unexpected regulatory link between the major energy-sensing kinase, membrane lipid composition, and transcription.

Highlights

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  AMPK/Snf1 inhibition of acetyl-CoA carboxylase controls fatty acyl-chain length

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  Opi1 repressor preferentially binds to C16 rather than C18 acyl-chains in PA

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  Acyl-chain length tunes Opi1 sequestration to the ER and target gene derepression

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  AMPK/Snf1 thus uses its effect on acyl-chain length to control Opi1 target genes

Abstract

Hofbauer et al. find that yeast Snf1/AMPK regulation of acetyl-CoA carboxylase affects acyl-chain length (C16 versus C18) in membrane phospholipids. Moreover, preferential binding of the transcriptional repressor Opi1 to C16-containing phosphatidic acid controls Opi1 sequestration and target gene derepression. Snf1/AMPK regulation of membrane-lipid composition thus determines a key transcriptional output.