Shaping proteostasis at the cellular, tissue, and organismal level

Sala, Ambre; Bott, Laura C.; Morimoto, Richard I.

doi:10.1083/jcb.201612111

Cited by 218 publications

(201 citation statements)

References 139 publications

(165 reference statements)

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“…Although the number of variants characterized in cellular models is limited, our observations show that the secretion defect correlates with distribution among REVEL clusters and supports the hypothesis that the secretion levels might correlate with REVEL scores in a continuous manner. The secretion levels observed in our two cell models, though broadly similar, differ for some tested variants, likely reflecting differences among cell types in the proteostatic mechanisms (Fra, Yoboue, & Sitia, 2017;Sala et al, 2017).…”

Section: Discussionmentioning

confidence: 63%

Real-world clinical applicability of pathogenicity predictors assessed onSERPINA1mutations in alpha-1-antitrypsin deficiency

et al. 2018

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The growth of publicly available data informing upon genetic variations, mechanisms of disease, and disease subphenotypes offers great potential for personalized medicine. Computational approaches are likely required to assess a large number of novel genetic variants. However, the integration of genetic, structural, and pathophysiological data still represents a challenge for computational predictions and their clinical use. We addressed these issues for alpha-1-antitrypsin deficiency, a disease mediated by mutations in the SERPINA1 gene encoding alpha-1-antitrypsin. We compiled a comprehensive database of SERPINA1 coding mutations and assigned them apparent pathological relevance based upon available data. "Benign" and "pathogenic" variations were used to assess performance of 31 pathogenicity predictors. Well-performing algorithms clustered the subset of variants known to be severely pathogenic with high scores. Eight new mutations identified in the ExAC database and achieving high scores were selected for characterization in cell models and showed secretory deficiency and polymer formation, supporting the predictive power of our computational approach. The behavior of the pathogenic new variants and consistent outliers were rationalized by considering the protein structural context and residue conservation. These findings highlight the potential of computational methods to provide meaningful predictions of the pathogenic significance of novel mutations and identify areas for further investigation.

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Section: Discussionmentioning

confidence: 63%

Real-world clinical applicability of pathogenicity predictors assessed onSERPINA1mutations in alpha-1-antitrypsin deficiency

et al. 2018

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“…Maintenance of cell proteome integrity relies on a sophisticated protein quality control system (PQC) that involves molecular chaperones and cellular degradation pathways (1,2). The cellular PQC system enables cells to prevent toxic protein aggregation, facilitate the assemblydisassembly of multiprotein complexes, and eliminate damaged components that result from mutations, genomic instability, or proteotoxic stress and aging.…”

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confidence: 99%

HSPB8 and BAG3 cooperate to promote spatial sequestration of ubiquitinated proteins and coordinate the cellular adaptive response to proteasome insufficiency

et al. 2018

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BCL2-associated athanogene (BAG)-3 is viewed as a platform that would physically and functionally link distinct classes of molecular chaperones of the heat shock protein (HSP) family for the stabilization and clearance of damaged proteins. In this study, we show that HSPB8, a member of the small heat shock protein subfamily, cooperates with BAG3 to coordinate the sequestration of harmful proteins and the cellular adaptive response upon proteasome inhibition. Silencing of HSPB8, like depletion of BAG3, inhibited targeting of ubiquitinated proteins to the juxtanuclear aggresome, a mammalian system of spatial quality control. However, aggresome targeting was restored in BAG3-depleted cells by a mutant BAG3 defective in HSPB8 binding, uncoupling HSPB8 function from its binding to BAG3. Depletion of HSPB8 impaired formation of ubiquitinated microaggregates in an early phase and interfered with accurate modifications of the stress sensor p62/sequestosome (SQSTM)-1. This impairment correlated with decreased coupling of BAG3 to p62/SQSTM1 in response to stress, hindering Kelch-like ECH-associated protein (KEAP)-1 sequestration and stabilization of nuclear factor E2-related factor (Nrf)-2, an important arm of the antioxidant defense. Notably, the myopathy-associated mutation of BAG3 (P209L), which lies within the HSPB8-binding motif, deregulated the association between BAG3 and p62/SQSTM1 and the KEAP1-Nrf2 signaling axis. Together, our findings support a so-far-unrecognized role for the HSPB8-BAG3 connection in mounting of an efficient stress response, which may be involved in BAG3-related human diseases.-Guilbert, S. M., Lambert, H., Rodrigue, M.-A., Fuchs, M., Landry, J., Lavoie, J. N. HSPB8 and BAG3 cooperate to promote spatial sequestration of ubiquitinated proteins and coordinate the cellular adaptive response to proteasome insufficiency.

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“…The abrupt collapse of proteostasis during early adulthood contributes to the wide-spread of heterogeneous responses to heat-shock Protein translation, trafficking and degradation are essential for the functionality of cellular processes. Upon a proteotoxic stress, such as heat-shock, the cell upregulates molecular chaperones, including HSP, to help re-establish protein homeostasis or proteostasis [46][47][48][49]. A natural decline in the activity of HSR and in survival to thermal stress in C. elegans coincides with a proteostasis collapse in multiple tissues, starting as early as 12 hours into adulthood (day-1 adults) [50][51][52].…”

Section: Time-lapse Imaging Reveals Heterogeneity In the Dynamics Ofmentioning

confidence: 99%

Heterogeneity in heat shock response dynamics caused by translation fidelity decline and proteostasis collapse

Vertti-Quintero

Berger

Solvas

et al. 2019

Preprint

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Genetics, environment, and stochasticity influence the rate of ageing in living organisms. Individual Caenorhabditis elegans that are genetically identical and cultured in the same environment have different lifespans, suggesting a significant role of stochasticity in ageing. We have developed a novel microfluidic methodology to measure heat-shock response as a surrogate marker for heterogeneity associated with lifespan and have quantified the heatshock response of C. elegans at the population, single individual, and tissue levels. We have further mathematically modelled our data to identify the major drivers determining such heterogeneity. This approach demonstrates that protein translation and degradation rate constants explain the individuality of the heat-shock time-course dynamic. We observed a decline of protein turnover capacity in early adulthood, co-incidentally occurring as the predicted proteostasis collapse. We identified a decline of intestinal response as the tissue that underlies the individual heterogeneity. Additionally, we verified that individuals with enhanced translation fidelity in early adulthood live longer. Altogether, our results reveal that the stochastic onset of proteostasis collapse of somatic tissues during early adulthood reflects individual protein translation capacity underlying heterogenic ageing of isogenic C. elegans.

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Shaping proteostasis at the cellular, tissue, and organismal level

Abstract: This review by Morimoto and colleagues examines mechanisms by which protein homeostasis (proteostasis) is achieved in multicellular organisms and discusses the implications for health and disease.

Cited by 218 publications

References 139 publications

Real-world clinical applicability of pathogenicity predictors assessed onSERPINA1mutations in alpha-1-antitrypsin deficiency

Real-world clinical applicability of pathogenicity predictors assessed onSERPINA1mutations in alpha-1-antitrypsin deficiency

HSPB8 and BAG3 cooperate to promote spatial sequestration of ubiquitinated proteins and coordinate the cellular adaptive response to proteasome insufficiency

Heterogeneity in heat shock response dynamics caused by translation fidelity decline and proteostasis collapse

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