Ribosome Collision Is Critical for Quality Control during No-Go Decay

Simms, Carrie L.; Yan, Liewei L.; Zaher, Hani

doi:10.1016/j.molcel.2017.08.019

Cited by 285 publications

(390 citation statements)

References 64 publications

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“…In this scenario, ribosomal collision and subsequent oligoribosome formation could be recognized as a signal of translational arrest, which is in complete agreement with earlier concepts and data by Simms and colleagues (Simms et al, 2017). In this scenario, ribosomal collision and subsequent oligoribosome formation could be recognized as a signal of translational arrest, which is in complete agreement with earlier concepts and data by Simms and colleagues (Simms et al, 2017).…”

supporting

confidence: 89%

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Collided ribosomes form a unique structural interface to induce Hel2‐driven quality control pathways

et al. 2019

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Ribosome stalling triggers quality control pathways targeting the mRNA (NGD: no‐go decay) and the nascent polypeptide (RQC: ribosome‐associated quality control). RQC requires Hel2‐dependent uS10 ubiquitination and the RQT complex in yeast. Here, we report that Hel2‐dependent uS10 ubiquitination and Slh1/Rqt2 are crucial for RQC and NGD induction within a di‐ribosome (disome) unit, which consists of the leading stalled ribosome and the following colliding ribosome. Hel2 preferentially ubiquitinated a disome over a monosome on a quality control inducing reporter mRNA in an in vitro translation reaction. Cryo‐EM analysis of the disome unit revealed a distinct structural arrangement suitable for recognition and modification by Hel2. The absence of the RQT complex or uS10 ubiquitination resulted in the elimination of NGD within the disome unit. Instead, we observed Hel2‐mediated cleavages upstream of the disome, governed by initial Not4‐mediated monoubiquitination of eS7 and followed by Hel2‐mediated K63‐linked polyubiquitination. We propose that Hel2‐mediated ribosome ubiquitination is required both for canonical NGD (NGDRQC+) and RQC coupled to the disome and that RQC‐uncoupled NGD outside the disome (NGDRQC−) can occur in a Not4‐dependent manner.

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supporting

confidence: 89%

“…Recent work has demonstrated that ribosome collision is a critical event triggering NGD, during which endonucleolytic cleavages in polysomes occur (Simms et al, 2017). Recent work has demonstrated that ribosome collision is a critical event triggering NGD, during which endonucleolytic cleavages in polysomes occur (Simms et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Collided ribosomes form a unique structural interface to induce Hel2‐driven quality control pathways

et al. 2019

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“…These findings are in complete agreement with two previous studies that showed a dependence on ribosome collision for Hel2 and ZNF598 activation (Simms et al, 2017b;Juszkiewicz et al, 2018). Previous proteomic analysis by the same group showed ribosomal protein uS10 to be a substrate for Hel2.…”

supporting

confidence: 92%

“…While initial models suggested that stalled ribosomes might exhibit a distinct conformation that is recognized by the E3 ligase, two recent studies have suggested that yeast Hel2 and its mammalian counterpart ZNF598 distinguish stalled ribosomes from normal ones by recognizing collided ribosomes (Simms et al, 2017b;Juszkiewicz et al, 2018). In particular, structural analysis by Juszkiewicz et al revealed that a collided di-ribosome (disome) provides an extensive interface between the leading and trailing 40S subunit for ZNF598 to recognize its target ribosomal proteins.…”

mentioning

confidence: 99%

Ubiquitin—a beacon for all during quality control on the ribosome

Yan

Zaher

2019

The EMBO Journal

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Ribosome stalling triggers no‐go decay (NGD) and ribosome‐associated quality control (RQC) pathways to rapidly degrade the aberrant mRNA and the incomplete nascent peptide, respectively. Two recent studies in yeast and mammalian systems reveal the importance of stalling‐induced ribosomal protein ubiquitination by Hel2/ZNF598 for both NGD and RQC. The studies also structurally explain how collided ribosomes generate a unique interface not present in monosomes, which can be recognized by Hel2/ZNF598 ubiquitin ligases.

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“…In particular, recent work has suggested that ribosomal collisions with the leading stalled ribosome are a key event that triggers the quality control responses that include decay of the mRNA ("No Go Decay" or NGD) and the nascent peptide (ribosome-associated quality control or RQC; Simms et al, 2017;Juszkiewicz et al, 2018;Ikeuchi et al, 2019). Considerable attention has been paid to the molecular consequences of the translating ribosomes encountering such mRNA sequences (i.e., the downstream quality control events that are triggered).…”

Section: Introductionmentioning

confidence: 99%

Molecular mechanism of translational stalling by inhibitory codon combinations and poly(A) tracts

et al. 2019

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Inhibitory codon pairs and poly(A) tracts within the translated mRNA cause ribosome stalling and reduce protein output. The molecular mechanisms that drive these stalling events, however, are still unknown. Here, we use a combination of in vitro biochemistry, ribosome profiling, and cryo-EM to define molecular mechanisms that lead to these ribosome stalls. First, we use an in vitro reconstituted yeast translation system to demonstrate that inhibitory codon pairs slow elongation rates which are partially rescued by increased tRNA concentration or by an artificial tRNA not dependent on wobble base-pairing. Ribosome profiling data extend these observations by revealing that paused ribosomes with empty A sites are enriched on these sequences. Cryo-EM structures of stalled ribosomes provide a structural explanation for the observed effects by showing decoding-incompatible conformations of mRNA in the A sites of all studied stall-and collision-inducing sequences. Interestingly, in the case of poly(A) tracts, the inhibitory conformation of the mRNA in the A site involves a nucleotide stacking array. Together, these data demonstrate a novel mRNA-induced mechanisms of translational stalling in eukaryotic ribosomes.

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Ribosome Collision Is Critical for Quality Control during No-Go Decay

Cited by 285 publications

References 64 publications

Collided ribosomes form a unique structural interface to induce Hel2‐driven quality control pathways

Collided ribosomes form a unique structural interface to induce Hel2‐driven quality control pathways

Ubiquitin—a beacon for all during quality control on the ribosome

Molecular mechanism of translational stalling by inhibitory codon combinations and poly(A) tracts

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