Sch9 regulates ribosome biogenesis via Stb3, Dot6 and Tod6 and the histone deacetylase complex RPD3L

Abstract

TORC1 is a conserved multisubunit kinase complex that regulates many aspects of eukaryotic growth including the biosynthesis of ribosomes. The TOR protein kinase resident in TORC1 is responsive to environmental cues and is potently inhibited by the natural product rapamycin. Recent characterization of the rapamycin-sensitive phosphoproteome in yeast has yielded insights into how TORC1 regulates growth. Here, we show that Sch9, an AGC family kinase and direct substrate of TORC1, promotes ribosome biogenesis (Ribi) and ribosomal protein (RP) gene expression via direct inhibitory phosphorylation of the transcriptional repressors Stb3, Dot6 and Tod6. Deletion of STB3, DOT6 and TOD6 partially bypasses the growth and cell size defects of an sch9 strain and reveals interdependent regulation of both Ribi and RP gene expression, and other aspects of Ribi. Dephosphorylation of Stb3, Dot6 and Tod6 enables recruitment of the RPD3L histone deacetylase complex to repress Ribi/RP gene promoters. Taken together with previous studies, these results suggest that Sch9 is a master regulator of ribosome biogenesis through the control of Ribi, RP, ribosomal RNA and tRNA gene transcription.

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Target of Rapamycin Complex 2 Regulates Actin Polarization and Endocytosis via Multiple Pathways

“…We previously used quantitative mass spectrometry to define the rapamycin-sensitive phosphoproteome of S. cerevisiae cells and identified many novel TORC1 effectors (11,62). Having a yeast-permeant TORC2 inhibitor allowed us to similarly ascertain the TORC2-dependent phosphoproteome by comparing the rapamycinsensitive phosphoproteome to the BHS345-sensitive phosphoproteome.…”

State Transitions in the TORC1 Signaling Pathway and Information Processing in Saccharomyces cerevisiae

“…The resulting Figure 1 Structure and function of the TORC1-dependent transcriptional network. (A) TORC1 acts through numerous downstream effector proteins to regulate protein and ribosome synthesis and a range of metabolic pathways (Martin et al 2004;Wullschleger et al 2006;Lempiainen et al 2009;Sengupta et al 2010;Huber et al 2011;Loewith and Hall 2011). The metabolic pathways are, to a large degree, regulated by the Tap42/PP2A protein phosphatases (Beck and Hall 1999;Jacinto et al 2001;Duvel et al 2003;Santhanam et al 2004;Huber et al 2009).…”

“…Specifically, it is known that when cells are grown in rich medium, TORC1 activates the S6 kinase Sch9, as well as several transcription factors (including Sfp1, Dot6/Tod6, Fhl1, Maf1, and Stb3; Figure 1A), to drive protein and ribosome synthesis (Upadhya et al 2002;Jorgensen et al 2004;Marion et al 2004;Schawalder et al 2004;Liko et al 2007;Urban et al 2007;Huber et al 2009;Lee et al 2009;Lempiainen et al 2009;Lippman and Broach 2009;Huber et al 2011). At the same time, active TORC1 binds and represses Tap42-PP2A, an activator of (i) the amino acid synthesis and nitrogen assimilation pathways via Npr1, Gln3, Rtg1/Rtg3, and other factors; (ii) the environmental stress response via Msn2/Msn4; and (iii) autophagy via Atg1 and/or other factors ( Figure 1A) (Di Como and Arndt 1996;Beck and Hall 1999;Crespo et al 2002;Duvel et al 2003;Santhanam et al 2004;Yan et al 2006;Shin et al 2009;Yorimitsu et al 2009;Breitkreutz et al 2010;Huber et al 2011). In contrast, when cells are starved for nitrogen or treated with rapamycin, TORC1 is inhibited so that protein/ ribosome synthesis halts while the cell synthesizes glutamine and other amino acids (Beck and Hall 1999;Cardenas et al 1999;Hardwick et al 1999;De Craene et al 2001;Crespo et al 2002;Duvel et al 2003;Huber et al 2009;Loewith and Hall 2011).…”