Yeast carbon catabolite repression

Abstract

Glucose and related sugars repress the transcription of genes encoding enzymes required for the utilization of alternative carbon sources; some of these genes are also repressed by other sugars such as galactose, and the process is known as catabolite repression. The different sugars produce signals which modify the conformation of certain proteins that, in turn, directly or through a regulatory cascade affect the expression of the genes subject to catabolite repression. These genes are not all controlled by a single set of regulatory proteins, but there are different circuits of repression for different groups of genes. However, the protein kinase Snf1/Cat1 is shared by the various circuits and is therefore a central element in the regulatory process. Snf1 is not operative in the presence of glucose, and preliminary evidence suggests that Snf1 is in a dephosphorylated state under these conditions. However, the enzymes that phosphorylate and dephosphorylate Snf1 have not been identified, and it is not known how the presence of glucose may affect their activity. What has been established is that Snf1 remains active in mutants lacking either the proteins Grr1/Cat80 or Hxk2 or the Glc7 complex, which functions as a protein phosphatase. One of the main roles of Snf1 is to relieve repression by the Mig1 complex, but it is also required for the operation of transcription factors such as Adr1 and possibly other factors that are still unidentified. Although our knowledge of catabolite repression is still very incomplete, it is possible in certain cases to propose a partial model of the way in which the different elements involved in catabolite repression may be integrated.

FIG. 1

Sequences of the Mig1 proteins from different yeasts which may be substrates of the protein kinase Snf1; the serine which may be phosphorylated is underlined. Amino acids which were found to be important in a study with artificial peptides as substrates for Snf1 (68) are shown in boldface type; amino acids in parentheses are suboptimal. Equivalent regions in the different proteins are aligned.

FIG. 2

Schematic view of the mode of action of Mig1 and its regulation. In the presence of glucose, Mig1 is found in the nucleus, where it represses the transcription of genes encoding activators such as GAL4 and MAL63 and of genes whose products are implicated in the metabolism of alternative carbon sources. Glucose removal causes both phosphorylation of Mig1, depending on the Snf1 complex, and its translocation to the cytoplasm. For details, see the text.

FIG. 3

Model for the regulation of the Snf1 complex by glucose. The bridging protein (Brp) between Snf1 and Snf4 can be Gal83, Sip1, Sip2, or some other, as yet unidentified, protein. Glucose affects the interaction between the catalytic domain (KD) and the regulatory domain (RD) of Snf1, presumably by inhibiting the (auto)phosphorylation of Snf1 and/or activating its dephosphorylation. Glucose may act at the level of the corresponding kinase and phosphatase but may also alter the conformation of Snf1 or even Brp, making Snf1 a worse or better substrate for the corresponding enzyme. Hxk2 and Grr1 are required for transmitting the glucose signal. Redrawn from reference .

FIG. 4

Control of the GAL genes by glucose in a gal80 background. In the presence of glucose, the Mig1 complex is active and decreases the rate of synthesis of GAL4 mRNA. The resulting low level of Gal4, together with the repressing effect of the Mig1 complex, leads to a very low level of expression of the GAL genes. For the Mig1 complex to exert its repressing activity, the Glc7 complex and elements in the glucose signalling pathway, such as Grr1 and Hxk2, are required. In the absence of glucose, the Snf1 complex is activated (see Fig. 3) and is able to release repression by Mig1; this allows maximal expression of GAL4, and the elevated levels of Gal4, together with the lack of activity of Mig1, turn on completely the expression of the GAL genes.

FIG. 5

Control of the FBP1 gene by glucose. In the presence of glucose, the Mig1 complex is active and Cat8 and the as yet unidentified activatory elements P1 and P2 are repressed; there is no expression of FBP1. When glucose is removed, the Snf1 complex is activated, and this results in release of repression by the Mig1 complex and derepression of Cat8. The expression and activation of the regulatory elements P1 and P2 depends on both Cat8 and an active Snf1 complex. Once P1 and P2 have been activated, they stimulate the transcription of FBP1.