Fus3-triggered Tec1 degradation modulates mating transciptional output during pheromone response

Department of Biological Chemistry, University of California, Irvine, CA 92697, USA.
Molecular Systems Biology (Impact Factor: 10.87). 02/2008; 4(1):212. DOI: 10.1038/msb.2008.47
Source: PubMed


The yeast transcription factor Ste12 controls both mating and filamentation pathways. Upon pheromone induction, the mitogen-activated protein kinases, Fus3 and Kss1, activate Ste12 by relieving the repression of two functionally redundant Ste12 inhibitors, Dig1 and Dig2. Mating genes are controlled by the Ste12/Dig1/Dig2 complex through Ste12-binding sites, whereas filamentation genes are regulated by the Tec1/Ste12/Dig1 complex through Tec1-binding sites. The two Ste12 complexes are mutually exclusive. During pheromone response, Tec1 is degraded upon phosphorylation by Fus3, preventing cross-activation of the filamentation pathway. Here, we show that a stable Tec1 also impairs the induction of mating genes. A mathematical model is developed to capture the dynamic formation of the two Ste12 complexes and their interactions with pathway-specific promoters. By model simulations and experimentation, we show that excess Tec1 can impair the mating transcriptional output because of its ability to sequester Ste12, and because of a novel function of Dig2 for the transcription of mating genes. We suggest that Fus3-triggered Tec1 degradation is an important part of the transcriptional induction of mating genes during the pheromone response.

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    • "In cells grown in SA, deletion of DIG1 and 2 also reduced the expression of the reporter gene, but only in haploid cells (Fig. 6A). These results suggest that Dig1, Dig2, or both are positive activators in agreement with recent reports demonstrating that Dig2 also functions as a positive regulator of genes controlled by the Pheromone-Response Element (PRE) [48], [49] through stabilization of its associated TF, Ste12 [49]. Thus, the repression of gene expression by Dig2 depends on its binding to the target gene’s promoter. "
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    • "Therefore, a potential mechanism for Dig2's positive role in transcriptional induction is that Dig2 prevents the formation of Ste12–Tec1 heterodimers, providing a larger pool of Ste12 multimers for activation of the mating transcriptional program. However, Chou et al (2008) found that Dig2's positive effect on transcription is independent of Tec1, eliminating this possibility. A second way that Dig2 could have a positive role in transcription would be for Dig2 to protect Ste12 from degradation. "
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    • "In S. cerevisiae, the Fus3-and the Kss1-related MAPK pathways converge on the Ste12 transcription factor to regulate mating or filamentation, respectively, in response to different stimuli. Signaling specificity is achieved by selective ubiquitination and sumoylation of Ste12 and its cofactor Tec1, leading to either degradation or protection of the respective transcription factors (Bruckner et al., 2004; Chou et al., 2008). Cross-activation of AtfA and OsrA in A. fumigatus could be prevented by a similar interplay between ubiquitination and sumoylation . "
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