Ageing exacerbates ribosome pausing to disrupt cotranslational proteostasis

Stein, Kevin C.; Morales-Polanco, Fabián; Lienden, Joris C J van der; Rainbolt, T. Kelly; Frydman, Judith

doi:10.1038/s41586-021-04295-4

Cited by 130 publications

(117 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Rapamycin acts by increasing autophagy and decreasing cellular senescence and senescenceassociated secretory phenotypes 55,[70][71][72] . It is noteworthy that all axes of proteostasis, including molecular chaperones, are overwhelmed by the accumulation of "difficultto-fold" or "difficult-to-degrade" proteins and aggregates in all degenerative physiological states, including during aging 2,24,73 . We speculate that rapamycin treatment may elevate the ratio of Hsp90β to substrate, and possibly that of Hsp90 to substrate if its mRNA can be shown to display some IRES activity.…”

Section: Discussionmentioning

confidence: 99%

Translational reprogramming in response to accumulating stressors ensures critical threshold levels of Hsp90 for mammalian life

Bhattacharya

Maiti

Zahorán

et al. 2022

Preprint

View full text Add to dashboard Cite

The cytosolic molecular chaperone Hsp90 is essential for eukaryotic life. It is involved in multiple branches of proteostasis, and as a molecular capacitor in morphological evolution. Although reduced Hsp90 levels cause phenotypic variations and correlate with aging, whether eukaryotic cells and organisms can tune the basal Hsp90 protein levels to alleviate physiologically accumulated stress is unknown. To begin to explore this question, we investigated whether and how mice adapt to the deletion of three out of four alleles encoding cytosolic Hsp90, one Hsp90β allele being the only remaining one. While the vast majority of such mouse embryos die during gestation, survivors apparently manage to increase their Hsp90β protein to at least wild-type levels. Further mechanistic studies revealed an internal ribosome entry site in the 5'UTR of the Hsp90β mRNA allowing translational reprogramming to compensate for the genetic loss of Hsp90 alleles and in response to stress. We found that the minimum amount of total Hsp90 that is required to support viability of mammalian cells and organisms is 50-70% of what is normally there. Those that fail to maintain a threshold level are subject to accelerated senescence, proteostatic collapse, and ultimately death. Therefore, considering that Hsp90 levels can be reduced ≥100-fold in the unicellular budding yeast, critical threshold levels of Hsp90 have been markedly increased during eukaryotic evolution. The incompressible part of the steady-state levels of Hsp90 may have increased to accommodate the ever-growing complexity of the proteome on the path towards mammals.

show abstract

Section: Discussionmentioning

confidence: 99%

Translational reprogramming in response to accumulating stressors ensures critical threshold levels of Hsp90 for mammalian life

Bhattacharya

Maiti

Zahorán

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Our findings point to a CAG-dependent elongation rate conflict as central to the etiology of HD. Interestingly, CAG repeats—one of the most common homopolymers in eukaryotic proteins—are frequently followed by polyproline stretches encoded by rare codons 53 . This is true for all kingdoms of life, including polyQ tracts in viruses 54 , suggesting a conserved and beneficial use of prolines to buffer the faster elongation on consecutive CAGs 11,55 .…”

Section: Discussionmentioning

confidence: 99%

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

Aviner

Lee

Masto

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…Notably, stalling on long poly-PR proteins is exacerbated when the global translation in compromised by adding elongation inhibitor. A recent study found that ageing, which is accompanied by a decline in cellular proteostasis, causes greater ribosome pausing at polybasic stretches (58). This suggests that a limited capacity that cells have to cope with stalls induced by a long poly-PR protein may be worse upon ageing and/or in the presence of other stresses, and therefore could prove as critical in the biological pathways leading to disease onset and development.…”

Section: Discussionmentioning

confidence: 99%

Arginine-rich C9ORF72 ALS Proteins Stall Ribosomes in a Manner Distinct From a Canonical Ribosome-Associated Quality Control Substrate

Kriachkov

McWilliam

Mintern

et al. 2022

Preprint

View full text Add to dashboard Cite

Hexanucleotide expansion mutations in C9ORF72 are a cause of familial amyotrophic lateral sclerosis. We previously reported that long arginine-rich dipeptide repeats (DPR), mimicking abnormal proteins expressed from the hexanucleotide expansion, caused translation stalling when expressed in cell culture models. Whether this stalling provides a mechanism of pathogenicity remains to be determined. Here we explored the molecular features of DPR-induced stalling and examined whether known regulatory mechanisms of ribosome quality control (RQC) are involved to sense and resolve the stalls. We demonstrate that arginine-containing DPRs lead to stalling in a length dependent manner, with lengths longer than 40 repeats invoking severe translation arrest. Mutational screening of 40xGly-Xxx DPRs shows that stalling is most pronounced where Xxx are positively charged amino acids (Arg or Lys). Through a genome-wide knockout screen we find that genes regulating stalling on polyadenosine mRNA coding for poly-Lys, a canonical RQC substrate, respond differently to the readthrough of arginine-rich DPRs. Indeed, we find evidence that DPR-mediated stalling has no natural regulatory responses even though the stalls may be sensed, as evidenced by an upregulation of RQC gene expression. These findings therefore implicate arginine-rich DPR-mediated stalled ribosomes as posing a particular danger to cellular health and viability.

show abstract

Ageing exacerbates ribosome pausing to disrupt cotranslational proteostasis

Cited by 130 publications

References 76 publications

Translational reprogramming in response to accumulating stressors ensures critical threshold levels of Hsp90 for mammalian life

Translational reprogramming in response to accumulating stressors ensures critical threshold levels of Hsp90 for mammalian life

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

Arginine-rich C9ORF72 ALS Proteins Stall Ribosomes in a Manner Distinct From a Canonical Ribosome-Associated Quality Control Substrate

Contact Info

Product

Resources

About