Transcriptional regulation of nonfermentable carbon utilization in budding yeast

Abstract

Saccharomyces cerevisiae preferentially uses glucose as a carbon source, but following its depletion, it can utilize a wide variety of other carbons including nonfermentable compounds such as ethanol. A shift to a nonfermentable carbon source results in massive reprogramming of gene expression including genes involved in gluconeogenesis, the glyoxylate cycle, and the tricarboxylic acid cycle. This review is aimed at describing the recent progress made toward understanding the mechanism of transcriptional regulation of genes responsible for utilization of nonfermentable carbon sources. A central player for the use of nonfermentable carbons is the Snf1 kinase, which becomes activated under low glucose levels. Snf1 phosphorylates various targets including the transcriptional repressor Mig1, resulting in its inactivation allowing derepression of gene expression. For example, the expression of CAT8, encoding a member of the zinc cluster family of transcriptional regulators, is then no longer repressed by Mig1. Cat8 becomes activated through phosphorylation by Snf1, allowing upregulation of the zinc cluster gene SIP4. These regulators control the expression of various genes including those involved in gluconeogenesis. Recent data show that another zinc cluster protein, Rds2, plays a key role in regulating genes involved in gluconeogenesis and the glyoxylate pathway. Finally, the role of additional regulators such as Adr1, Ert1, Oaf1, and Pip2 is also discussed.

Fig. 1

Metabolic pathways and genes involved in the utilization of nonfermentable carbons. Metabolic pathways for utilization of nonfermentable carbons are schematically shown as well as key genes involved in this process. The pathway for fatty acid metabolism was omitted (see Hiltunen et al., 2003 for a review). Arrows with full lines correspond to enzymatic reactions while arrows with dashed lines correspond to regulatory steps. STL1 and JEN2 encode membrane transporters for glycerol and lactate, respectively. SFC1 encodes a mitochondrial transporter for fumarate. More information for specific genes can be found at the yeast genome database (http://www.yeastgenome.org).

Fig. 2

Limited overlap between Rds2 and Cat8 target genes. Cat8 target genes identified by ChIP-chip analysis under low glucose conditions (Tachibana et al., 2005) were compared with those identified for Rds2 under ethanol (Soontorngun et al., 2007) or lactate conditions (N. Soontorngun & B. Turcotte, unpublished data). P-values used for gene selection are indicated below Venn diagrams.

Fig. 3

A model for the regulatory network of regulators of nonfermentable carbons. Low glucose levels activate the Snf1 kinase, resulting in phosphorylation and inactivation of the Mig1 repressor. Cat8, Sip4, and Rds2 are also substrates of Snf1. Rds2 and probably Gsm1 are activators of HAP4, whose gene product is a part of a complex involved in the positive control of CAT8 and GSM1. Cat8 and most likely Rds2 are positive regulators of SIP4. CAT8 expression is probably autoregulated. Cat8, Sip4, Rds2, Ert1, and Gsm1 are all transcriptional regulators of PCK1 encoding a key gluconeogenic enzyme. ChIP analysis showed that Rds2 binds to the OPI1 gene encoding a repressor of GUT1 and GUT2 expression involved in glycerol metabolism. See text for more details.