TOR Regulates Ribosomal Protein Gene Expression via PKA and the Forkhead Transcription Factor FHL1

Abstract

The regulation of ribosome biogenesis in response to environmental conditions is a key aspect of cell growth control. Ribosomal protein (RP) genes are regulated by the nutrient-sensitive, conserved target of rapamycin (TOR) signaling pathway. TOR controls the subcellular localization of protein kinase A (PKA) and the PKA-regulated kinase YAK1. However, the target transcription factor(s) of the TOR-PKA pathway are unknown. We show that regulation of RP gene transcription via TOR and PKA in yeast involves the Forkhead-like transcription factor FHL1 and the two cofactors IFH1 (a coactivator) and CRF1 (a corepressor). TOR, via PKA, negatively regulates YAK1 and maintains CRF1 in the cytoplasm. Upon TOR inactivation, activated YAK1 phosphorylates and activates CRF1. Phosphorylated CRF1 accumulates in the nucleus and competes with IFH1 for binding to FHL1 at RP gene promoters, and thereby inhibits transcription of RP genes. Thus, we describe a signaling mechanism linking an environmental sensor to ribosome biogenesis.

Revisiting the role of yeast Sfp1 in ribosome biogenesis and cell size control: a chemostat study

“…For the RP genes, Rap1 together with the Fhl1-Ifh1 complex is the main transcriptional regulator (Klein & Struhl, 1994;Martin et al, 2004;Rudra et al, 2005). The activity of all these factors is regulated via partially overlapping pathways (involving TOR and PKA), allowing a coordinate expression of all the components required for ribosome biosynthesis.…”

Life in the midst of scarcity: adaptations to nutrient availability in Saccharomyces cerevisiae

“…Concerning the regulation of RP gene transcription by RNA polymerase II, it was found that TORC1 promotes complex formation between Fhl1, a forkhead-like transcription factor that binds to the promoter of RP genes, and its co-activator Ifh1 (Lee et al 2002;Martin et al 2004;Schawalder et al 2004;Wade et al 2004;Rudra et al 2005). This Fhl1-Ifh1 complex then promotes the expression of RP genes.…”

Rearrangements of the transcriptional regulatory networks of metabolic pathways in fungi

“…While the utilization of metabolites such as sugars and lipids could be easily seen to be subject to differential regulatory pressures based on the metabolic niche of the organism, the expression of ribosomal protein genes is a highly conserved and universal process, and thus it is remarkable that the regulatory circuits controlling this process have been fundamentally rewired between S. cerevisiae and C. albicans.I nS. cerevisiae the regulatory circuit controlling the expression of ribosomal proteins consists of the generalist myb-domain containing transcription factor Rap1p together with the high-mobility group protein Hmo1p and a condition-sensitive switch complex made up of Ifh1 and Fhl1 [47][48][49][50][51]. In C. albicans, the Ifh1/Fhl1 switch appears to be conserved, but the key DNA-binding element of the circuit is the myb-domain protein Tbf1 ( [22 ] Lavoie et al, submitted) ( Figure 2c).…”