Harmonizing ribosomal proteins and rRNA

Sci. Signal.  29 Nov 2016:
Vol. 9, Issue 456, pp. ec282
DOI: 10.1126/scisignal.aal4635

Synthesis of ribosomes is one of the most energy-intensive cellular processes, requiring the coordinated synthesis of ribosomal RNA (rRNA) and dozens of ribosomal proteins (RPs). In yeast, RP genes (RPGs) are expressed when the activator protein Ifh1 binds to the transcription factor Fhl1, which is constitutively bound to RPG promoters. Inhibition of growth with rapamycin (a drug that inhibits the nutrient-sensing and growth-controlling kinase target of rapamycin [TOR]) or by nutrient depletion triggers Ifh1 dissociation from RPG promoters, reducing transcription of RPGs. Ifh1 also exists in a complex called CURI that includes two proteins involved in rRNA processing. Studying the yeast Saccharomyces cerevisiae, Albert et al. found that a direct interaction between Ifh1 and Utp22, an rRNA-processing protein in the CURI complex, played an essential role in coordinating RP and rRNA synthesis. In yeast two-hybrid assays, Ihf1 associated with Utp22. Chromatin immunoprecipitation with sequencing (ChIP-seq) showed that Ihf1 binds to the UTP22 promoter, and analysis of yeast in which Ihf1 was depleted from the nucleus confirmed that Ihf1 regulates the transcription of UTP22 in addition to regulating RPG transcription. In yeast strains containing a mutation that reduces the interaction of Ifh1 with Fhl1 at RPG promoters, inducible overexpression of Utp22 impeded growth, whereas overexpression of another protein from the CURI complex did not. In cells that had been depleted of the induced Utp22 and then were exposed to rapamycin to inhibit TOR, Ifh1 associated with RPG promoters within 20 minutes of the addition of rapamycin, a time at which Ifh1 continued to be dissociated from RPG promoters in wild-type yeast exposed to rapamycin. Rapid rebinding of Ifh1 to RPG promoters in response to Utp22-depletion also occurred in yeast growing under starvation conditions (deficiency of glucose or both glucose and amino acids), suggesting that Utp22 is specifically required for long-term repression of RP synthesis under conditions that inhibit the nutrient-sensing TOR pathway. Consistent with this model, expression of an Ihf1 mutant that could not bind Utp22 resulted in the return of Ifh1 to RPG promoters in yeast exposed to rapamycin. The interaction of Ifh1 with RPG promoters is dynamic, with a Utp22-independent component occurring within 5 minutes of rapamycin treatment. Thus, Ihf1 both stimulates expression of the Utp22-encoding gene and binds Utp22 in a complex necessary for restricting transcription of RPGs. By sequestering Ihf1 away from RPG promoters, Utp22 enables cells to properly coordinate RPG expression with growth conditions. What effect Ihf1 has on the rRNA-processing functions of Utp22 remains to be determined. Rudra and Warner discuss the extent to which these proteins and interactions are conserved in mammalian cells and raise the possibility that different mechanisms may coordinate rRNA and RP synthesis in different eukaryotes.

B. Albert, B. Knight, J. Merwin, V. Martin, D. Ottoz, Y. Gloor, M. J. Bruzzone, A. Rudner, D. Shore, A molecular titration system coordinates ribosomal protein gene transcription with ribosomal RNA synthesis. Mol. Cell 64, 720–733 (2016). [PubMed]

D. Rudra, J. R. Warner, A CURIous case of molecular kidnapping. Mol. Cell 64, 639–640 (2016). [PubMed]

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