A ribosome assembly stress response regulates transcription to maintain proteome homeostasis

• Published in: eLife Vol. 8
• Main Authors: Albert, Benjamin, Kos-Braun, Isabelle C, Henras, Anthony K, Dez, Christophe, Rueda, Maria Paula, Zhang, Xu, Gadal, Olivier, Kos, Martin, Shore, David
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 24-05-2019; eLife Sciences Publications Ltd; eLife Sciences Publication; eLife Sciences Publications, Ltd
• Subjects: Biochemistry, Molecular Biology; Biosynthesis; Cell Biology; Cell growth; Chromosomes and Gene Expression; Control systems; Gene expression; Gene Expression Regulation, Fungal; Genes; Genomics; heat shock factor 1; Heat shock proteins; Homeostasis; Housing; HSF1 protein; Hsp70 protein; Hybridization; Ifh1; Kinases; Life Sciences; Molecular biology; Observations; Organelle Biogenesis; Physiological aspects; protein aggregation; Proteins; Proteomes; Proteostasis; Quality control; ribosomal protein; Ribosomal RNA; ribosome biogenesis; Ribosomes; Ribosomes - metabolism; RNA; RNA polymerase; rRNA; Saccharomyces cerevisiae - physiology; Saccharomyces cerevisiae Proteins - biosynthesis; Stress response; Stress, Physiological; topoisomerase; Transcription (Genetics); Transcription activation; Transcription, Genetic; Yeast; United States; cell biology; Ifh1; protein aggregation; chromosomes; heat shock factor 1; topoisomerase; ribosomal protein; gene expression; S. cerevisiae; ribosome biogenesis
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.45002

Ribosome biogenesis is a complex and energy-demanding process requiring tight coordination of ribosomal RNA (rRNA) and ribosomal protein (RP) production. Given the extremely high level of RP synthesis in rapidly growing cells, alteration of any step in the ribosome assembly process may impact growth by leading to proteotoxic stress. Although the transcription factor Hsf1 has emerged as a central regulator of proteostasis, how its activity is coordinated with ribosome biogenesis is unknown. Here, we show that arrest of ribosome biogenesis in the budding yeast
triggers rapid activation of a highly specific stress pathway that coordinately upregulates Hsf1 target genes and downregulates RP genes. Activation of Hsf1 target genes requires neo-synthesis of RPs, which accumulate in an insoluble fraction and presumably titrate a negative regulator of Hsf1, the Hsp70 chaperone. RP aggregation is also coincident with that of the RP gene activator Ifh1, a transcription factor that is rapidly released from RP gene promoters. Our data support a model in which the levels of newly synthetized RPs, imported into the nucleus but not yet assembled into ribosomes, work to continuously balance Hsf1 and Ifh1 activity, thus guarding against proteotoxic stress during ribosome assembly.