bims-proarb Biomed News
on Proteostasis in aging and regenerative biology
Issue of 2023‒01‒22
eight papers selected by
Rich Giadone
Harvard University
  1. Ending a bad start: Triggers and mechanisms of co-translational protein degradation.
  2. Balanced activities of Hsp70 and the ubiquitin proteasome system underlie cellular protein homeostasis.
  3. Stem cell factors reverse signs of aging in mice.
  4. Age-Related Dysfunction in Proteostasis and Cellular Quality Control in the Development of Sarcopenia.
  5. Genome-wide RNA polymerase stalling shapes the transcriptome during aging.
  6. In-Depth Proteomic Analysis of De Novo Proteome in a Mouse Model of Alzheimer's Disease.
  7. Blood-to-brain communication in aging and rejuvenation.
  8. Mammalian life depends on two distinct pathways of DNA damage tolerance.
  1. Front Mol Biosci. 2022 ;9 1089825
    Ending a bad start: Triggers and mechanisms of co-translational protein degradation.
    Tom Joshua Eisenack, Débora Broch Trentini.
      Proteins are versatile molecular machines that control and execute virtually all cellular processes. They are synthesized in a multilayered process requiring transfer of information from DNA to RNA and finally into polypeptide, with many opportunities for error. In addition, nascent proteins must successfully navigate a complex folding-energy landscape, in which their functional native state represents one of many possible outcomes. Consequently, newly synthesized proteins are at increased risk of misfolding and toxic aggregation. To maintain proteostasis-the state of proteome balance-cells employ a plethora of molecular chaperones that guide proteins along a productive folding pathway and quality control factors that direct misfolded species for degradation. Achieving the correct balance between folding and degradation therefore represents a fundamental task for the proteostasis network. While many chaperones act co-translationally, protein quality control is generally considered to be a post-translational process, as the majority of proteins will only achieve their final native state once translation is completed. Nevertheless, it has been observed that proteins can be ubiquitinated during synthesis. The extent and the relevance of co-translational protein degradation, as well as the underlying molecular mechanisms, remain areas of open investigation. Recent studies made seminal advances in elucidating ribosome-associated quality control processes, and how their loss of function can lead to proteostasis failure and disease. Here, we discuss current understanding of the situations leading to the marking of nascent proteins for degradation before synthesis is completed, and the emerging quality controls pathways engaged in this task in eukaryotic cells. We also highlight the methods used to study co-translational quality control.
    Keywords:  membrane insertion; protein folding; quality control; ribosome stalling; translation; ubiquitin
    DOI:  https://doi.org/10.3389/fmolb.2022.1089825
  2. Front Mol Biosci. 2022 ;9 1106477
    Balanced activities of Hsp70 and the ubiquitin proteasome system underlie cellular protein homeostasis.
    Areeb Jawed, Chi-Ting Ho, Tomas Grousl, Aseem Shrivastava, Thomas Ruppert, Bernd Bukau, Axel Mogk.
      To counteract proteotoxic stress and cellular aging, protein quality control (PQC) systems rely on the refolding, degradation and sequestration of misfolded proteins. In Saccharomyces cerevisiae the Hsp70 chaperone system plays a central role in protein refolding, while degradation is predominantly executed by the ubiquitin proteasome system (UPS). The sequestrases Hsp42 and Btn2 deposit misfolded proteins in cytosolic and nuclear inclusions, thereby restricting the accessibility of misfolded proteins to Hsp70 and preventing the exhaustion of limited Hsp70 resources. Therefore, in yeast, sequestrase mutants show negative genetic interactions with double mutants lacking the Hsp70 co-chaperone Fes1 and the Hsp104 disaggregase (fes1Δ hsp104Δ, ΔΔ) and suffering from low Hsp70 capacity. Growth of ΔΔbtn2Δ mutants is highly temperature-sensitive and results in proteostasis breakdown at non-permissive temperatures. Here, we probed for the role of the ubiquitin proteasome system in maintaining protein homeostasis in ΔΔbtn2Δ cells, which are affected in two major protein quality control branches. We show that ΔΔbtn2Δ cells induce expression of diverse stress-related pathways including the ubiquitin proteasome system to counteract the proteostasis defects. Ubiquitin proteasome system dependent degradation of the stringent Hsp70 substrate firefly Luciferase in the mutant cells mirrors such compensatory activities of the protein quality control system. Surprisingly however, the enhanced ubiquitin proteasome system activity does not improve but aggravates the growth defects of ΔΔbtn2Δ cells. Reducing ubiquitin proteasome system activity in the mutant by lowering the levels of functional 26S proteasomes improved growth, increased refolding yield of the Luciferase reporter and attenuated global stress responses. Our findings indicate that an imbalance between Hsp70-dependent refolding, sequestration and ubiquitin proteasome system-mediated degradation activities strongly affects protein homeostasis of Hsp70 capacity mutants and contributes to their severe growth phenotypes.
    Keywords:  26S proteasome; Hsp70; chaperone; protein quality control; protein sequestration
    DOI:  https://doi.org/10.3389/fmolb.2022.1106477
  3. Science. 2023 Jan 20. 379(6629): 224
    Stem cell factors reverse signs of aging in mice.
    Catherine Offord.
      Will reprogramming technique one day help people?
    DOI:  https://doi.org/10.1126/science.adg7353
  4. Cells. 2023 Jan 07. pii: 249. [Epub ahead of print]12(2):
    Age-Related Dysfunction in Proteostasis and Cellular Quality Control in the Development of Sarcopenia.
    Hector G Paez, Christopher R Pitzer, Stephen E Alway.
      Sarcopenia is a debilitating skeletal muscle disease that accelerates in the last decades of life and is characterized by marked deficits in muscle strength, mass, quality, and metabolic health. The multifactorial causes of sarcopenia have proven difficult to treat and involve a complex interplay between environmental factors and intrinsic age-associated changes. It is generally accepted that sarcopenia results in a progressive loss of skeletal muscle function that exceeds the loss of mass, indicating that while loss of muscle mass is important, loss of muscle quality is the primary defect with advanced age. Furthermore, preclinical models have suggested that aged skeletal muscle exhibits defects in cellular quality control such as the degradation of damaged mitochondria. Recent evidence suggests that a dysregulation of proteostasis, an important regulator of cellular quality control, is a significant contributor to the aging-associated declines in muscle quality, function, and mass. Although skeletal muscle mammalian target of rapamycin complex 1 (mTORC1) plays a critical role in cellular control, including skeletal muscle hypertrophy, paradoxically, sustained activation of mTORC1 recapitulates several characteristics of sarcopenia. Pharmaceutical inhibition of mTORC1 as well as caloric restriction significantly improves muscle quality in aged animals, however, the mechanisms controlling cellular proteostasis are not fully known. This information is important for developing effective therapeutic strategies that mitigate or prevent sarcopenia and associated disability. This review identifies recent and historical understanding of the molecular mechanisms of proteostasis driving age-associated muscle loss and suggests potential therapeutic interventions to slow or prevent sarcopenia.
    Keywords:  aging; anabolic resistance; atrophy; autophagy; caloric restriction; dynapenia; mTORC1; mitochondria; mitophagy; muscle protein synthesis; rapamycin; sarcopenia; skeletal muscle; ubiquitin proteasome
    DOI:  https://doi.org/10.3390/cells12020249
  5. Nat Genet. 2023 Jan 19.
    Genome-wide RNA polymerase stalling shapes the transcriptome during aging.
    Akos Gyenis, Jiang Chang, Joris J P G Demmers, Serena T Bruens, Sander Barnhoorn, Renata M C Brandt, Marjolein P Baar, Marko Raseta, Kasper W J Derks, Jan H J Hoeijmakers, Joris Pothof.
      Gene expression profiling has identified numerous processes altered in aging, but how these changes arise is largely unknown. Here we combined nascent RNA sequencing and RNA polymerase II chromatin immunoprecipitation followed by sequencing to elucidate the underlying mechanisms triggering gene expression changes in wild-type aged mice. We found that in 2-year-old liver, 40% of elongating RNA polymerases are stalled, lowering productive transcription and skewing transcriptional output in a gene-length-dependent fashion. We demonstrate that this transcriptional stress is caused by endogenous DNA damage and explains the majority of gene expression changes in aging in most mainly postmitotic organs, specifically affecting aging hallmark pathways such as nutrient sensing, autophagy, proteostasis, energy metabolism, immune function and cellular stress resilience. Age-related transcriptional stress is evolutionary conserved from nematodes to humans. Thus, accumulation of stochastic endogenous DNA damage during aging deteriorates basal transcription, which establishes the age-related transcriptome and causes dysfunction of key aging hallmark pathways, disclosing how DNA damage functionally underlies major aspects of normal aging.
    DOI:  https://doi.org/10.1038/s41588-022-01279-6
  6. J Alzheimers Dis. 2023 Jan 11.
    In-Depth Proteomic Analysis of De Novo Proteome in a Mouse Model of Alzheimer's Disease.
    Xin Wang, Xueyan Zhou, Jingyun Lee, Cristina M Furdui, Tao Ma.
      BACKGROUND: Alzheimer's disease (AD) is the most common dementia syndrome in the elderly characterized by synaptic failure and unique brain pathology. De novo protein synthesis is required for the maintenance of memory and synaptic plasticity. Mounting evidence links impaired neuronal protein synthesis capacity and overall protein synthesis deficits to AD pathogenesis. Meanwhile, identities of AD-associated dysregulation of "newly synthesized proteome" remain elusive.OBJECTIVE: To investigate de novo proteome alterations in the hippocampus of aged Tg19959 AD model mice.
    METHODS: In this study, we combined the bioorthogonal noncanonical amino acid tagging (BONCAT) method with the unbiased large-scale proteomic analysis in acute living brain slices (we name it "BONSPEC") to investigate de novo proteome alterations in the hippocampus of Tg19959 AD model mice. We further applied multiple bioinformatics methods to analyze in-depth the proteomics data.
    RESULTS: In total, 1,742 proteins were detected across the 10 samples with the BONSPEC method. After exclusion of those only detected in less than half of the samples in both groups, 1,362 proteins were kept for further analysis. 37 proteins were differentially expressed (based on statistical analysis) between the WT and Tg19959 groups. Among them, 19 proteins were significantly decreased while 18 proteins were significantly increased in the hippocampi of Tg19959 mice compared to WT mice. The results suggest that proteins involved in synaptic function were enriched in de novo proteome of AD mice.
    CONCLUSION: Our study could provide insights into the future investigation into the molecular signaling mechanisms underlying AD and related dementias (ADRDs).
    Keywords:  Aging; Alzheimer’s disease; mass spectrometry; protein synthesis; proteomics
    DOI:  https://doi.org/10.3233/JAD-221044
  7. Nat Neurosci. 2023 Jan 16.
    Blood-to-brain communication in aging and rejuvenation.
    Gregor Bieri, Adam B Schroer, Saul A Villeda.
      Aging induces molecular, cellular and functional changes in the adult brain that drive cognitive decline and increase vulnerability to dementia-related neurodegenerative diseases. Leveraging systemic and lifestyle interventions, such as heterochronic parabiosis, administration of 'young blood', exercise and caloric restriction, has challenged prevalent views of brain aging as a rigid process and has demonstrated that aging-associated cognitive and cellular impairments can be restored to more youthful levels. Technological advances in proteomic and transcriptomic analyses have further facilitated investigations into the functional impact of intertissue communication on brain aging and have led to the identification of a growing number of pro-aging and pro-youthful factors in blood. In this review, we discuss blood-to-brain communication from a systems physiology perspective with an emphasis on blood-derived signals as potent drivers of both age-related brain dysfunction and brain rejuvenation.
    DOI:  https://doi.org/10.1038/s41593-022-01238-8
  8. Proc Natl Acad Sci U S A. 2023 Jan 24. 120(4): e2216055120
    Mammalian life depends on two distinct pathways of DNA damage tolerance.
    Olimpia Alessandra Buoninfante, Bas Pilzecker, Aldo Spanjaard, Daniël de Groot, Stefan Prekovic, Ji-Ying Song, Cor Lieftink, Matilda Ayidah, Colin E J Pritchard, Judith Vivié, Kathleen E Mcgrath, Ivo J Huijbers, Sjaak Philipsen, Marieke von Lindern, Wilbert Zwart, Roderick L Beijersbergen, James Palis, Paul C M van den Berk, Heinz Jacobs.
      DNA damage threatens genomic integrity and instigates stem cell failure. To bypass genotoxic lesions during replication, cells employ DNA damage tolerance (DDT), which is regulated via PCNA ubiquitination and REV1. DDT is conserved in all domains of life, yet its relevance in mammals remains unclear. Here, we show that inactivation of both PCNA-ubiquitination and REV1 results in embryonic and adult lethality, and the accumulation of DNA damage in hematopoietic stem and progenitor cells (HSPCs) that ultimately resulted in their depletion. Our results reveal the crucial relevance of DDT in the maintenance of stem cell compartments and mammalian life in unperturbed conditions.
    Keywords:  DNA damage response (DDR); DNA damage tolerance (DDT); embryonic lethality; erythropoiesis; hematopoietic stem cells
    DOI:  https://doi.org/10.1073/pnas.2216055120
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