bims-proarb Biomed News
on Proteostasis in aging and regenerative biology
Issue of 2022–04–17
twelve papers selected by
Rich Giadone, Harvard University
  1. What's next for AlphaFold and the AI protein-folding revolution.
  2. Folding or Holding? - Hsp70 and Hsp90 chaperoning of misfolded proteins in neurodegenerative disease.
  3. Itaconate prolongs the healthy lifespan by activating UPRmt in Caenorhabditis elegans.
  4. Chaperone-Mediated Autophagy in Neurodegenerative Diseases and Acute Neurological Insults in the Central Nervous System.
  5. Proteomes of primary skin fibroblasts from healthy individuals reveal altered cell responses across the life span.
  6. From Alpha to Beta - a co-translational way to fold?
  7. Hidden information on protein function in censuses of proteome foldedness.
  8. Association of the Protein-Quality-Control Protein Ubiquilin-1 With Alzheimer's Disease Both in vitro and in vivo.
  9. Automated, high-dimensional evaluation of physiological aging and resilience in outbred mice.
  10. [HSP90α exacerbates house dust mite-induced asthmatic airway inflammation by upregulating endoplasmic reticulum stress in bronchial epithelial cells].
  11. Why do naked mole rats live as long as giraffes?
  12. The Roles of NEDD4 Subfamily of HECT E3 Ubiquitin Ligases in Neurodevelopment and Neurodegeneration.
  1. Nature. 2022 Apr;604(7905): 234-238
    What's next for AlphaFold and the AI protein-folding revolution.
    Ewen Callaway.
      
    Keywords:  Biological techniques; Computational biology and bioinformatics; Drug discovery; Structural biology
    DOI:  https://doi.org/10.1038/d41586-022-00997-5
  2. J Biol Chem. 2022 Apr 06. pii: S0021-9258(22)00345-3. [Epub ahead of print] 101905
    Folding or Holding? - Hsp70 and Hsp90 chaperoning of misfolded proteins in neurodegenerative disease.
    Benjamin S Rutledge, Wing-Yiu Choy, Martin L Duennwald.
      The toxic accumulation of misfolded proteins as inclusions, fibrils, or aggregates is a hallmark of many neurodegenerative diseases. However, how molecular chaperones, such as Hsp70 and Hsp90, defend cells against the toxic consequences of protein misfolding remains unclear. The ATP-dependent foldase function of both Hsp70 and Hsp90 actively transitions the toxic misfolded proteins back to their native conformation. By contrast, the ATP-independent holdase function of Hsp70 and Hsp90 prevents the toxic accumulation of misfolded proteins. Foldase and holdase functions can protect against the toxicity associated with protein misfolding, yet we are only beginning to understand the underlying mechanisms and how they modulate neurodegeneration. In his review, we compare recent structural findings regarding the binding of Hsp90 to misfolded and intrinsically disordered proteins, such as tau, α-synuclein, and TDP-43. We propose that Hsp90 and to some extent Hsp70 interact with these proteins through an extended and dynamic interface that span the surface of multiple domains of the chaperone proteins. This contrasts with many other Hsp90-client protein interactions for which only a single bound conformation of Hsp90 is proposed. The dynamic nature of these multi-domain interactions allows polymorphic binding of multiple conformations to vast regions of Hsp90. The holdase functions of Hsp70 and Hsp90 may thus allow neuronal cells to modulate misfolded proteins more energy efficient by reducing the long-term ATP running costs of the chaperone budget. However, it remains unclear whether holdase functions protect cells by preventing aggregate formation or can increase neurotoxicity by inadvertently stabilizing deleterious oligomers.
    Keywords:  Hsp90; TDP-43; alpha-synuclein; intrinsically disordered proteins; molecular chaperones; tau
    DOI:  https://doi.org/10.1016/j.jbc.2022.101905
  3. Eur J Pharmacol. 2022 Apr 08. pii: S0014-2999(22)00212-6. [Epub ahead of print]923 174951
    Itaconate prolongs the healthy lifespan by activating UPRmt in Caenorhabditis elegans.
    Qingqing Wang, Hongyuan Li, Gangwei Zhang, Xiaoguang Chen, Xiaohui Wang.
      Itaconate (ItA), a byproduct of the Krebs cycle, has recently emerged as an anti-inflammatory metabolite for inhibiting the overactive immune response. In addition to its immunomodulatory and antimicrobial effects, ItA may have other therapeutic avenues. Herein, the effect of ItA on aging was explored in order to better establish the therapeutic potential of this promising metabolite. ItA extended the lifespan and enhanced the stress resistance of Caenorhabditis elegans (C. elegans), even at the doses of 0.01 and 0.1 μM. Moreover, the lifespan extension effect of ItA was pronounced even for the aged worms (days 7 and 9 post adult stage). Furthermore, ItA was found to extend the healthy longevity of C. elegans in a mitochondria-dependent manner. ItA protected the mitochondrial integrity, increased ATP content, and decreased the reactive oxygen species (ROS) in C. elegans. Mechanistic investigations showed that ItA specifically activated the mitochondrial unfolded protein response (UPRmt) in worms and significantly increased the expression of activating transcription factor associated with stress-1 (ATFS-1) that senses mitochondrial stress and communicates with the nucleus during the UPRmt. ItA extended the lifespan of C. elegans in an ATFS-1-dependent manner. In summary, this study elucidates the molecular mechanism by which ItA extends the healthy lifespan and highlights the importance of mitochondrial integrity in the intervention of aging.
    Keywords:  Activating transcription factor associated with stress-1; Caenorhabditis elegans; Healthy span; Itaconate; Mitochondrial unfolded protein response
    DOI:  https://doi.org/10.1016/j.ejphar.2022.174951
  4. Cells. 2022 Apr 02. pii: 1205. [Epub ahead of print]11(7):
    Chaperone-Mediated Autophagy in Neurodegenerative Diseases and Acute Neurological Insults in the Central Nervous System.
    Haruo Kanno, Kyoichi Handa, Taishi Murakami, Toshimi Aizawa, Hiroshi Ozawa.
      Autophagy is an important function that mediates the degradation of intracellular proteins and organelles. Chaperone-mediated autophagy (CMA) degrades selected proteins and has a crucial role in cellular proteostasis under various physiological and pathological conditions. CMA dysfunction leads to the accumulation of toxic protein aggregates in the central nervous system (CNS) and is involved in the pathogenic process of neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. Previous studies have suggested that the activation of CMA to degrade aberrant proteins can provide a neuroprotective effect in the CNS. Recent studies have shown that CMA activity is upregulated in damaged neural tissue following acute neurological insults, such as cerebral infarction, traumatic brain injury, and spinal cord injury. It has been also suggested that various protein degradation mechanisms are important for removing toxic aberrant proteins associated with secondary damage after acute neurological insults in the CNS. Therefore, enhancing the CMA pathway may induce neuroprotective effects not only in neurogenerative diseases but also in acute neurological insults. We herein review current knowledge concerning the biological mechanisms involved in CMA and highlight the role of CMA in neurodegenerative diseases and acute neurological insults. We also discuss the possibility of developing CMA-targeted therapeutic strategies for effective treatments.
    Keywords:  Alzheimer’s disease; Hsc70; LAMP2A; Parkinson’s disease; autophagy; central nervous system; chaperone-mediated autophagy; neurodegenerative disease; spinal cord injury; traumatic brain injury
    DOI:  https://doi.org/10.3390/cells11071205
  5. Aging Cell. 2022 Apr 15. e13609
    Proteomes of primary skin fibroblasts from healthy individuals reveal altered cell responses across the life span.
    Dimitrios Tsitsipatis, Jennifer L Martindale, Ceereena Ubaida-Mohien, Alexey Lyashkov, Hagai Yanai, Amogh Kashyap, Chang Hoon Shin, Allison B Herman, Eunbyul Ji, Jen-Hao Yang, Rachel Munk, Christopher Dunn, Yevgeniya Lukyanenko, Xiaoling Yang, Chee W Chia, Ajoy C Karikkineth, Linda Zukley, Jarod D'Agostino, Mary Kaileh, Chang-Yi Cui, Isabel Beerman, Luigi Ferrucci, Myriam Gorospe.
      Changes in the proteome of different human tissues with advancing age are poorly characterized. Here, we studied the proteins present in primary skin fibroblasts collected from 82 healthy individuals across a wide age spectrum (22-89 years old) who participated in the GESTALT (Genetic and Epigenetic Signatures of Translational Aging Laboratory Testing) study of the National Institute on Aging, NIH. Proteins were extracted from lysed fibroblasts and subjected to liquid chromatography-mass spectrometry analysis, and the expression levels of 9341 proteins were analyzed using linear regression models. We identified key pathways associated with skin fibroblast aging, including autophagy, scavenging of reactive oxygen species (ROS), ribosome biogenesis, DNA replication, and DNA repair. Changes in these prominent pathways were corroborated using molecular and cell culture approaches. Our study establishes a framework of the global proteome governing skin fibroblast aging and points to possible biomarkers and therapeutic targets.
    Keywords:  DNA damage; DNA repair; aging; autophagy; human dermal fibroblasts; proteomics; reactive oxygen species; ribosome biogenesis
    DOI:  https://doi.org/10.1111/acel.13609
  6. Cell Cycle. 2022 Apr 11. 1-4
    From Alpha to Beta - a co-translational way to fold?
    Anton A Komar.
      Protein folding in the cell is largely a co-translational process occurring during protein synthesis on the ribosome. It has become evident that co-translational folding is characteristic to almost every protein in the cell of pro- and eukaryotic origin that are single and multidomain, single and multisubunit, cytosolic, secretory and membrane. Co-translational protein folding begins very early during the process of polypeptide chain synthesis on the ribosome, with some secondary structure elements forming inside the ribosomal tunnel and some tertiary structures forming inside the vestibule (lower/wider) region of the ribosomal exit tunnel. However, many details of co-translational folding remains incompletely understood. New data show that folding of a β-barrel protein begins with formation of an α-helix inside the ribosome that rearranges into a β-hairpin structure as the growing peptide reaches the wider/vestibule region of the exit tunnel. While it was previously suggested that such scenario can take place on the ribosome, the new data provide the first experimental evidence in support of this notion.
    Keywords:  Co-translational folding; ribosomal tunnel; structural interconversion; α-helix; β-barrel protein
    DOI:  https://doi.org/10.1080/15384101.2022.2062186
  7. Nat Commun. 2022 Apr 14. 13(1): 1992
    Hidden information on protein function in censuses of proteome foldedness.
    Dezerae Cox, Ching-Seng Ang, Nadinath B Nillegoda, Gavin E Reid, Danny M Hatters.
      Methods that assay protein foldedness with proteomics have generated censuses of apparent protein folding stabilities in biological milieu. However, different censuses poorly correlate with each other. Here, we show that the reason for this is that methods targeting foldedness through monitoring amino acid sidechain reactivity also detect changes in conformation and ligand binding, which can be a substantial fraction of the data. We show that the reactivity of only one quarter of cysteine or methionine sidechains in proteins in a urea denaturation curve of mammalian cell lysate can be confidently explained by a two-state unfolding isotherm. Contrary to that expected from unfolding, up to one third of the cysteines decreased reactivity. These cysteines were enriched in proteins with functions relating to unfolded protein stress. One protein, chaperone HSPA8, displayed changes arising from ligand and cofactor binding. Unmasking this hidden information using the approaches outlined here should improve efforts to understand both folding and the remodeling of protein function directly in complex biological settings.
    DOI:  https://doi.org/10.1038/s41467-022-29661-2
  8. Front Neurosci. 2022 ;16 821059
    Association of the Protein-Quality-Control Protein Ubiquilin-1 With Alzheimer's Disease Both in vitro and in vivo.
    Can Zhang, Shivangi M Inamdar, Swathi Swaminathan, Daniel R Marenda, Aleister J Saunders.
      Alzheimer's disease (AD) belongs to a class of diseases characterized by progressive accumulation and aggregation of pathogenic proteins, particularly Aβ proteins. Genetic analysis has identified UBQLN1 as an AD candidate gene. Ubiquilin-1 levels reduce with AD progression, suggesting a potential loss-of-function mechanism. The ubiquilin-1 protein is involved in protein quality control (PQC), which plays essential roles in cellular growth and normal cell function. Ubiquilin-1 regulates γ-secretase by increasing endoproteolysis of PS1, a key γ-secretase component. Presently, the effects of ubiquilin-1 on cellular physiology as well as Aβ-related events require further investigation. Here, we investigated the effects of ubiquilin-1 on cellular growth and viability in association with APP (amyloid-β protein precursor), APP processing-related β-secretase (BACE1, BACE) and γ-secretase using cell and animal-based models. We showed that loss-of-function in Drosophila ubqn suppresses human APP and human BACE phenotypes in wing veins and altered cell number and tissue compartment size in the wing. Additionally, we performed cell-based studies and showed that silencing UBQLN1 reduced cell viability and increased caspase-3 activity. Overexpression of UBQLN1 significantly reduced Aβ levels. Furthermore, pharmacological inhibition of γ-secretase increased ubiquilin-1 protein levels, suggesting a mechanism that regulates ubiquilin-1 levels which may associate with reduced Aβ reduction by inhibiting γ-secretase. Collectively, our results support not only a loss-of-function mechanism of ubiquilin-1 in association with AD, but also support the significance of targeting ubiquilin-1-mediated PQC as a potential therapeutic strategy for AD.
    Keywords:  APP – amyloid precursor protein; Alzheimer’s disease; Drosophila; gamma secretase (γ-secretase); ubiquilin 1 (UBQLN1)
    DOI:  https://doi.org/10.3389/fnins.2022.821059
  9. Elife. 2022 Apr 11. pii: e72664. [Epub ahead of print]11
    Automated, high-dimensional evaluation of physiological aging and resilience in outbred mice.
    Zhenghao Chen, Anil Raj, G V Prateek, Andrea Di Francesco, Justin Liu, Brice E Keyes, Ganesh Kolumam, Vladimir Jojic, Adam Freund.
      Behavior and physiology are essential readouts in many studies but have not benefited from the high-dimensional data revolution that has transformed molecular and cellular phenotyping. To address this, we developed an approach that combines commercially available automated phenotyping hardware with a systems biology analysis pipeline to generate a high-dimensional readout of mouse behavior/physiology, as well as intuitive and health-relevant summary statistics (resilience and biological age). We used this platform to longitudinally evaluate aging in hundreds of outbred mice across an age range from 3 months to 3.4 years. In contrast to the assumption that aging can only be measured at the limits of animal ability via challenge-based tasks, we observed widespread physiological and behavioral aging starting in early life. Using network connectivity analysis, we found that organism-level resilience exhibited an accelerating decline with age that was distinct from the trajectory of individual phenotypes. We developed a method, Combined Aging and Survival Prediction of Aging Rate (CASPAR), for jointly predicting chronological age and survival time and showed that the resulting model is able to predict both variables simultaneously, a behavior that is not captured by separate age and mortality prediction models. This study provides a uniquely high-resolution view of physiological aging in mice and demonstrates that systems-level analysis of physiology provides insights not captured by individual phenotypes. The approach described here allows aging, and other processes that affect behavior and physiology, to be studied with improved throughput, resolution, and phenotypic scope.
    Keywords:  aging; computational biology; healthspan; mouse; physiology; resilience; systems biology
    DOI:  https://doi.org/10.7554/eLife.72664
  10. Nan Fang Yi Ke Da Xue Xue Bao. 2022 Mar 20. 42(3): 347-353
    [HSP90α exacerbates house dust mite-induced asthmatic airway inflammation by upregulating endoplasmic reticulum stress in bronchial epithelial cells].
    H Huang, Y Qiao, Y Huang, H Dong.
       OBJECTIVE: To explore the role of heat shock protein 90α (HSP90α) and endoplasmic reticulum (ER) stress pathway in allergic airway inflammation induced by house dust mite (HDM) in bronchial epithelial cells.
    METHODS: A HDM- induced asthmatic cell model was established in human bronchial epithelial (HBE) cells by exposure to a concentration gradient (200, 400 and 800 U/mL) of HDM for 24 h. To test the effect of siHSP90α and HSP90 inhibitor 17-AAG on HDM-induced asthmatic inflammation, HBE cells were transfected with siHSP90α (50 nmol, 12 h) or pretreated with 17-AAG (900 nmol, 6 h) prior to HDM exposure (800 U/mL) for 24 h, and the changes in the expression of HSP90α and ER stress markers were assessed. We also tested the effect of nasal drip of 17-AAG, HDM, or their combination on airway inflammation and ER stress in C57BL/6 mice.
    RESULTS: In HBE cells, HDM exposure significantly up-regulated the expression of HSP90α protein (P=0.011) and ER stress markers XBP-1 (P=0.044), ATF-6α (P=0.030) and GRP-78 (P=0.027). Knocking down HSP90α and treatment with 17-AAG both significantly inhibited HDM-induced upregulation of XBP-1 (P=0.008). In C57BL/6 mice, treatment with 17-AAG obviously improved HDM-induced airway inflammation and significantly reduced the number of inflammatory cells in the airway (P=0.014) and lowered the levels of IL-4 (P=0.030) and IL-5 (P=0.035) in alveolar lavage fluid. Immunohistochemical staining showed that the expressions of XBP-1 and GRP-78 in airway epithelial cells decreased significantly after the treatment of 17-AAG.
    CONCLUSIONS: HSP90α promotes HDM-induced airway allergic inflammation possibly by upregulating ER stress pathway in bronchial epithelial cells.
    Keywords:  asthma; endoplasmic reticulum stress; heat shock protein 90α; house dust mite
    DOI:  https://doi.org/10.12122/j.issn.1673-4254.2022.03.05
  11. Nature. 2022 Apr 13.
    Why do naked mole rats live as long as giraffes?
      
    Keywords:  Ageing; Genetics; Particle physics
    DOI:  https://doi.org/10.1038/d41586-022-01062-x
  12. Int J Mol Sci. 2022 Mar 31. pii: 3882. [Epub ahead of print]23(7):
    The Roles of NEDD4 Subfamily of HECT E3 Ubiquitin Ligases in Neurodevelopment and Neurodegeneration.
    Shanez Haouari, Patrick Vourc'h, Médéric Jeanne, Sylviane Marouillat, Charlotte Veyrat-Durebex, Débora Lanznaster, Frédéric Laumonnier, Philippe Corcia, Hélène Blasco, Christian R Andres.
      The ubiquitin pathway regulates the function of many proteins and controls cellular protein homeostasis. In recent years, it has attracted great interest in neurodevelopmental and neurodegenerative diseases. Here, we have presented the first review on the roles of the 9 proteins of the HECT E3 ligase NEDD4 subfamily in the development and function of neurons in the central nervous system (CNS). We discussed their regulation and their direct or indirect involvement in neurodevelopmental diseases, such as intellectual disability, and neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease or Amyotrophic Lateral Sclerosis. Further studies on the roles of these proteins, their regulation and their targets in neurons will certainly contribute to a better understanding of neuronal function and dysfunction, and will also provide interesting information for the development of therapeutics targeting them.
    Keywords:  ALS; development; intellectual disability; ligases; neurodegenerative; ubiquitin
    DOI:  https://doi.org/10.3390/ijms23073882
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