A ribosome assembly stress response regulates transcription to maintain proteome homeostasis

Abstract

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 Saccharomyces cerevisiae 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.

ATAC-Seq Identifies Chromatin Landscapes Linked to the Regulation of Oxidative Stress in the Human Fungal Pathogen Candida albicans

“…Cluster 4 included regions with decreased chromatin accessibility upstream of the TSS in response to H 2 O 2 treatment ( Figure 2 C,D, dark blue line in panel D). Genes from this cluster were involved in ribosome- and translation-related processes ( Supplementary Figure S2A ), most of which are often downregulated during fungal stress adaptation [ 69 , 70 , 71 , 72 , 73 ].…”

Translation elongation factor 2 depletion by siRNA in mouse liver leads to mTOR-independent translational upregulation of ribosomal protein genes

“…Stoichiometry of ribosomal proteins has to be well maintained in cells due to the large production volume and therefore high energy requirements. It is achieved through various mechanisms at the level of transcription, translation (TOP motif), and degradation 45 . The severely impaired yield of translation may lead to a decrease in protein degradation to preserve the remaining proteins.…”

Mosaic changes to the global transcriptome in response to inhibiting ribosome formation versus inhibition of ribosome function

“…R-protein synthesis is repressed after the abolition of rRNA synthesis due to the accumulation of aggregates of r-proteins that fail to be assembled in the absence of de novo rRNA synthesis (Albert et al 2019a). Most likely, the initial decrease in the mean expression of r-protein genes after cessation of uL4 synthesis is actuated by this mechanism.…”

“…During extreme stress, another kinase, ZAKa, phosphorylates map kinases resulting in apoptosis and cell death (Vind et al 2020;Wu et al 2020). Another pathway limiting expression of rprotein genes is actuated by obstruction of ribosome assembly, which causes accumulation of insoluble aggregates of ribosomal and other proteins including Ifh1 (Albert et al 2019a).…”