Molecular Highway Patrol for Ribosome Collisions

Iyer, Keerthana; Müller, Max; Tittel, Lena Sophie; Winz, Marie‐Luise

doi:10.1002/cbic.202300264

Cited by 4 publications

(1 citation statement)

References 180 publications

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“…The RQC process can be divided into initiation (splitting of the stalled ribosome), elongation (extension of the nascent polypeptide with a degron tag) and termination (release of the tagged protein) phases. Both in eukaryotes and bacteria, ribosomal collisions serve as a substrate that is efficiently recognised by the RQC machinery 31,36,37 . In B. subtilis, rescue of stalled and collided ribosomes (disomes) is initiated by the dimeric MutS2/RqcU ATPase that splits the leading (stalled) ribosome into subunits, thereby generating a free 30S subunit and a 50S-nascent chain complex, 50S-NCC 31 .…”

Section: Introductionmentioning

confidence: 99%

A role for the S4-domain containing protein YlmH in ribosome-associated quality control inBacillus subtilis

Takada,

Paternoga,

Fujiwara

et al. 2024

Preprint

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Ribosomes trapped on mRNAs during protein synthesis need to be rescued for the cell to survive. The most ubiquitous bacterial ribosome rescue pathway is trans-translation mediated by tmRNA and SmpB. Genetic inactivation of trans-translation can be lethal, unless the ribosomes are rescued by ArfA or ArfB alternative rescue factors or the ribosome-associated quality control (RQC) system, which inB. subtilisinvolves MutS2, RqcH, RqcP and Pth. Using transposon sequencing in a trans-translation-incompetentB. subtilisstrain we identify a poorly characterized S4-domain-containing protein YlmH as a novel potential RQC factor. Cryo-EM structures reveal that YlmH binds peptidyl-tRNA-50S complexes in an position analogous to that of S4-domain-containing RqcP, and that, similarly to RqcP, YlmH can co-habit with RqcH. Consistently, we show that YlmH can assume the role of RqcP in RQC in facilitating the addition of polyalanine tails to the truncated nascent polypeptides. While inB. subtilisthe function of YlmH is redundant with RqcP, our taxonomic analysis reveals that in multiple bacterial phyla RqcP is absent, while YlmH and RqcH are present, suggesting that in these species the YlmH plays a central role in the RQC.

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Section: Introductionmentioning

confidence: 99%

A role for the S4-domain containing protein YlmH in ribosome-associated quality control inBacillus subtilis

Takada,

Paternoga,

Fujiwara

et al. 2024

Preprint

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Transcriptional profile of ribosome-associated quality control components and their associated phenotypes in mammalian cells

Dos Santos,

Carneiro,

Requião

et al. 2024

Sci Rep

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During protein synthesis, organisms detect translation defects that induce ribosome stalling and result in protein aggregation. The Ribosome-associated Quality Control (RQC) complex, comprising TCF25, LTN1, and NEMF, is responsible for identifying incomplete protein products from unproductive translation events, targeting them for degradation. Although RQC disruption causes adverse effects on vertebrate neurons, data regarding mRNA/protein expression and regulation across tissues are lacking. Employing high-throughput methods, we analyzed public datasets to explore RQC gene expression and phenotypes. Our findings revealed widespread expression of RQC components in human tissues; however, silencing of RQC yielded only mild negative effects on cell growth. Notably, TCF25 exhibited elevated mRNA levels that were not reflected in the protein content. We experimentally demonstrated that this disparity arose from post-translational protein degradation by the proteasome. Additionally, we observed that cellular aging marginally influenced RQC expression, leading to reduced mRNA levels in specific tissues. Our results suggest the necessity of RQC expression in all mammalian tissues. Nevertheless, when RQC falters, alternative mechanisms seem to compensate, ensuring cell survival under nonstress conditions.

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Evidence that Xrn1 is in complex with Gcn1, and is required for full levels of eIF2α phosphorylation

Shanmugam,

Anderson,

Schiemann

et al. 2024

Biochemical Journal

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The protein kinase Gcn2 and its effector protein Gcn1 are part of the General Amino Acid Control signalling (GAAC) pathway best known in yeast for its function in maintaining amino acid homeostasis. Under amino acid limitation, Gcn2 becomes activated, subsequently increasing the levels of phosphorylated eIF2α (eIF2α-P). This leads to the increased translation of transcriptional regulators, such as Gcn4 in yeast and ATF4 in mammals, and subsequent re-programming of the cell’s gene transcription profile, thereby allowing cells to cope with starvation. Xrn1 is involved in RNA decay, quality control and processing. We found that Xrn1 co-precipitates Gcn1 and Gcn2, suggesting that these three proteins are in the same complex. Growth under starvation conditions was dependent on Xrn1 but not on Xrn1-ribosome association, and this correlated with reduced eIF2α-P levels. Constitutively active Gcn2 leads to a growth defect due to eIF2α-hyperphosphorylation, and we found that this phenotype was independent of Xrn1, suggesting that xrn1 deletion doesn’t enhance eIF2α de-phosphorylation. Our study provides evidence that Xrn1 is required for efficient Gcn2 activation, directly or indirectly. Thus, we have uncovered a potential new link between RNA metabolism and the GAAC.

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Molecular Highway Patrol for Ribosome Collisions

Cited by 4 publications

References 180 publications

A role for the S4-domain containing protein YlmH in ribosome-associated quality control inBacillus subtilis

A role for the S4-domain containing protein YlmH in ribosome-associated quality control inBacillus subtilis

Transcriptional profile of ribosome-associated quality control components and their associated phenotypes in mammalian cells

Evidence that Xrn1 is in complex with Gcn1, and is required for full levels of eIF2α phosphorylation

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