Detecting and Rescuing Stalled Ribosomes

Yip, M.C.J.; Shao, Sichen

doi:10.1016/j.tibs.2021.03.008

Cited by 52 publications

(33 citation statements)

References 101 publications

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“…Similar to our viral mHtt-ex1(Q73) (Fig. 2d), expression of an expanded polyQ tract increased polysome association of the Gcn1-Gcn20-Rbg2 complex, which binds collided ribosomes 32 . Importantly, we also observed decreased association of eIF5A in the polyQ(111) cells (Fig.…”

Section: Mainsupporting

confidence: 79%

Ribotoxic collisions on CAG expansions disrupt proteostasis and stress responses in Huntington’s Disease

Aviner

Lee

Masto

et al. 2022

Preprint

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Huntington's disease (HD) is a devastating neurodegenerative disorder caused by CAG trinucleotide repeat expansions encoding a polyglutamine (polyQ) tract in the Huntingtin (HTT) gene1. Although mutant HTT (mHTT) protein tends to aggregate, the exact causes of neurotoxicity in HD remain unclear2. Here we show that altered elongation kinetics on CAG expansions cause ribosome collisions that trigger ribotoxicity, proteotoxicity and maladaptive stress responses. CAG expansions cause an elongation rate conflict during HTT translation, when ribosomes rapidly decoding the optimal polyQ encounter a flanking slowly-decoded polyproline tract. The ensuing ribosome collisions lead to premature termination and release of aggregation-prone mHTT fragments. Due to the presence of a stress-responsive upstream open reading frame (uORF), HTT translation and aggregation are limited under normal conditions but enhanced under stress, seeding a vicious cycle of dysfunction. mHTT further exacerbates ribotoxicity by progressively sequestering eIF5A, a key regulator of translation elongation, polyamine metabolism and stress responses. eIF5A depletion in HD cells leads to widespread ribosome pausing on eIF5A-dependent sites, impaired cotranslational proteostasis, disrupted polyamine metabolism and maladaptive stress responses. Importantly, drugs that reduce translation initiation attenuate ribosome collisions and mitigate this escalating cascade of ribotoxic stress and dysfunction in HD.

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Section: Mainsupporting

confidence: 79%

Ribotoxic collisions on CAG expansions disrupt proteostasis and stress responses in Huntington’s Disease

Aviner

Lee

Masto

et al. 2022

Preprint

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“…The ribosome exit tunnel regulates translation and protein folding ( 106 – 108 ). Certain amino acid sequence segments are also known to stall ribosomes ( 109 , 110 ). In a study on the proteomes of multiple organisms by Requião R.D.…”

Section: Discussionmentioning

confidence: 99%

Net Charges of the Ribosomal Proteins of the S10 and spc Clusters of Halophiles Are Inversely Related to the Degree of Halotolerance

Tirumalai

Anane-Bediakoh

Rajesh³

et al. 2021

Microbiol Spectr

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The net charges (at pH 7.4) of the ribosomal proteins (r-proteins) that comprise the S10-spc cluster show an inverse relationship with the halophilicity/halotolerance levels in both bacteria and archaea. In non-halophilic bacteria, the S10-spc cluster r-proteins are generally basic (positively charged), while the rest of the proteomes in these strains are generally acidic.

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“…The ribosome exit tunnel regulates translation and protein folding (109)(110)(111). Certain amino acid sequence segments are also known to stall ribosomes (112,113). In a study on the proteomes of multiple organisms by Requião RD et al (114), negatively charged proteins were found to be overrepresented.…”

Section: Implications Of Net Charges On Translational Rate(s) and Ribosome Stabilitymentioning

confidence: 99%

Net charges of the ribosomal proteins of theS10andspcclusters of halophiles are inversely related to the degree of halotolerance

Tirumalai

Anane-Bediakoh

Rajesh³

et al. 2021

Preprint

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Net positive charge(s) on ribosomal proteins (r-proteins) have been reported to influence the assembly and folding of ribosomes. A high percentage of r-proteins from extremely halophilic archaea are known to be acidic or even negatively charged. Those proteins that remain positively charged are typically far less so. Herein the analysis is extended to the non-archaeal halophilic bacteria, eukaryotes and halotolerant archaea. The net charges (pH 7.4) of r-proteins that comprise the S10-spc operon/cluster from individual microbial and eukaryotic genomes were estimated and intercompared. It was observed that as a general rule, as the salt tolerance of the bacterial strains increased from 5 to 15%, the net charges of the individual proteins remained mostly basic. The most striking exceptions were the extremely halophilic bacterial strains, Salinibacter ruber SD01, Acetohalobium arabaticum DSM 5501 and Selenihalanaerobacter shriftii ATCC BAA-73, which are reported to require a minimum of 18%-21% of salt for their growth. All three strains have a higher number of acidic S10-spc cluster r-proteins than what is seen in the moderate halophiles or the halotolerant strains. Of the individual proteins, only uL2 never became acidic. uS14 and uL16 also seldom became acidic. The net negative charges on several of the S10-spc cluster r-proteins is a feature generally shared by all extremely halophilic archaea and bacteria. The S10-spc cluster r-proteins of halophilic fungi and algae (eukaryotes) were exceptions. They were positively charged despite the halophilicity of the organisms.ImportanceThe net charges (at pH 7.4) of the ribosomal proteins (r-proteins) that comprise the S10-spc cluster show an inverse relationship with the halophilicity/halotolerance levels in both bacteria and archaea. In non-halophilic bacteria, the S10-spc cluster r-proteins are generally basic (positively charged), while the rest of the proteomes in these strains are generally acidic. On the other hand, the whole proteomes of the extremely halophilic strains are overall negatively charged including the S10-spc cluster r-proteins. Given that the distribution of charged residues in the ribosome exit tunnel influences co-translational folding, the contrasting charges observed in the S10-spc cluster r-proteins has potential implications for the rate of passage of these proteins through the ribosomal exit tunnel. Furthermore, the universal protein uL2 which lies in the oldest part of the ribosome is always positively charged irrespective of the strain/organism it belongs to. This has implications for its role in the prebiotic context.

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Detecting and Rescuing Stalled Ribosomes

Cited by 52 publications

References 101 publications

Ribotoxic collisions on CAG expansions disrupt proteostasis and stress responses in Huntington’s Disease

Ribotoxic collisions on CAG expansions disrupt proteostasis and stress responses in Huntington’s Disease

Net Charges of the Ribosomal Proteins of the S10 and spc Clusters of Halophiles Are Inversely Related to the Degree of Halotolerance

Net charges of the ribosomal proteins of theS10andspcclusters of halophiles are inversely related to the degree of halotolerance

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