Bacterial ribosome collision sensing by a MutS DNA repair ATPase paralogue

Cerullo, Federico; Filbeck, Sebastian; Patil, Pratik Rajendra; Hung, Hao-Chih; Xu, Haowen; Vornberger, Julia; Hofer, Florian W.; Schmitt, Jaro; Bukau, Bernd; Hofmann, Kay; Pfeffer, Stefan; Joazeiro, Claudio A.P.

doi:10.1038/s41586-022-04487-6

Cited by 39 publications

(48 citation statements)

References 66 publications

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“…Importantly, the observed mechanism is highly specific in that it works only on ribosomes with a collided neighbor and requires licensing/recruitment through ubiquitin tagging of the stalled ribosome. These ideas are in line with the recent discovery in the bacterium Bacillus subtilis of an alternative splitting factor, the ATPase MutS2, that clears collided ribosomes ( 44 ). Although its mode of function is not entirely clear yet, it appears to function independent of mRNA, thereby making the RQT mechanism a unique example of an mRNA helicase dependent ribosomal splitting device which is conserved in eukaryotes from fungus to humans.…”

Section: Resultssupporting

confidence: 69%

Clearing of ribosome collisions by the ribosome quality control trigger complex RQT

Best¹,

Ikeuchi²,

Kater³

et al. 2022

Preprint

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After translational stalls, colliding eukaryotic ribosomes are cleared through dissociation into subunits by the ribosome quality control trigger complex, RQT, by an unknown mechanism. Here we show that RQT requires accessible mRNA and the presence of a neighboring ribosome. Cryo-EM of several RQT-ribosome complexes revealed the structural basis of splitting: RQT engages the 40S subunit of the lead ribosome and can switch between two conformations. We propose a mechanistic model in which the Slh1 helicase subunit of RQT applies a pulling force on the mRNA, causing destabilizing conformational changes of the 40S subunit. The collided ribosome functions as a ram or giant wedge, ultimately resulting in subunit dissociation. Our findings provide a first conceptual framework for a helicase driven ribosomal splitting mechanism.One-Sentence SummaryRQT clears collided ribosomes by pulling mRNA to trigger destabilizing conformational transitions for subunit dissociation.

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Section: Resultssupporting

confidence: 69%

Clearing of ribosome collisions by the ribosome quality control trigger complex RQT

Best¹,

Ikeuchi²,

Kater³

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Importantly, the observed mechanism is highly specific in that it works only on ribosomes with a collided neighbor and requires licensing/recruitment through ubiquitin tagging of the stalled ribosome. These ideas are in line with the recent discovery in the bacterium Bacillus subtilis of an alternative splitting factor, the ATPase MutS2, that clears collided ribosomes 54 . Although its mode of function is not entirely clear yet, it appears to function independent of mRNA, thereby making the RQT mechanism a unique example of an mRNA helicase-dependent ribosomal splitting device which is conserved in eukaryotes from fungus to humans.…”

Section: Discussionsupporting

confidence: 68%

Structural basis for clearing of ribosome collisions by the RQT complex

Best¹,

Ikeuchi²,

Kater

et al. 2023

Nat Commun

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Translation of aberrant messenger RNAs can cause stalling of ribosomes resulting in ribosomal collisions. Collided ribosomes are specifically recognized to initiate stress responses and quality control pathways. Ribosome-associated quality control facilitates the degradation of incomplete translation products and requires dissociation of the stalled ribosomes. A central event is therefore the splitting of collided ribosomes by the ribosome quality control trigger complex, RQT, by an unknown mechanism. Here we show that RQT requires accessible mRNA and the presence of a neighboring ribosome. Cryogenic electron microscopy of RQT-ribosome complexes reveals that RQT engages the 40S subunit of the lead ribosome and can switch between two conformations. We propose that the Ski2-like helicase 1 (Slh1) subunit of RQT applies a pulling force on the mRNA, causing destabilizing conformational changes of the small ribosomal subunit, ultimately resulting in subunit dissociation. Our findings provide conceptual framework for a helicase-driven ribosomal splitting mechanism.

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“…Moreover, collided ribosomes in mammals elicit general stress responses (Wu et al, 2020) and the innate immune signaling (Wan et al, 2021), emphasizing the importance of quality control systems in preventing over-activation of signaling pathways that sometimes result in cell death. In bacteria, where the ubiquitin system is absent, the endonuclease SmrB and the ATPase MutS have been lately identified as collision sensors that rescue stalled ribosomes by promoting subunit dissociation and mRNA cleavages, respectively (Cerullo et al, 2022;Saito et al, 2022).…”

Section: Introductionmentioning

confidence: 99%