bims-proarb Biomed News
on Proteostasis in aging and regenerative biology
Issue of 2022–12–18
nine papers selected by
Rich Giadone, Harvard University
  1. HSP70-HSP90 Chaperone Networking in Protein-Misfolding Disease.
  2. Role of Proteostasis Regulation in the Turnover of Stress Granules.
  3. Endoplasmic Reticulum Stress Signaling and Neuronal Cell Death.
  4. Co-chaperones of the Human Endoplasmic Reticulum: An Update.
  5. Protein biosynthesis at the ER: finding the right accessories.
  6. Discovery and Development of a Selective Inhibitor of the ER Resident Chaperone Grp78.
  7. CPNE1 regulates myogenesis through the PERK-eIF2α pathway mediated by endoplasmic reticulum stress.
  8. Glycoprotein (GP)96 is essential for maintaining intestinal epithelial architecture by supporting its self-renewal capacity.
  9. Cell Surface Membrane Lipid Rafts as Potent Regulators of Stem Cell Proliferation, Differentiation, Trafficking and Metabolism.
  1. Subcell Biochem. 2023 ;101 389-425
    HSP70-HSP90 Chaperone Networking in Protein-Misfolding Disease.
    Chrisostomos Prodromou, Xavi Aran-Guiu, Jasmeen Oberoi, Laura Perna, J Paul Chapple, Jacqueline van der Spuy.
      Molecular chaperones and their associated co-chaperones are essential in health and disease as they are key facilitators of protein-folding, quality control and function. In particular, the heat-shock protein (HSP) 70 and HSP90 molecular chaperone networks have been associated with neurodegenerative diseases caused by aberrant protein-folding. The pathogenesis of these disorders usually includes the formation of deposits of misfolded, aggregated protein. HSP70 and HSP90, plus their co-chaperones, have been recognised as potent modulators of misfolded protein toxicity, inclusion formation and cell survival in cellular and animal models of neurodegenerative disease. Moreover, these chaperone machines function not only in folding but also in proteasome-mediated degradation of neurodegenerative disease proteins. This chapter gives an overview of the HSP70 and HSP90 chaperones, and their respective regulatory co-chaperones, and explores how the HSP70 and HSP90 chaperone systems form a larger functional network and its relevance to counteracting neurodegenerative disease associated with misfolded proteins and disruption of proteostasis.
    Keywords:  Chaperone; Co-chaperones; HSP70; HSP90; Neurodegeneration; Protein degradation; Protein quality control
    DOI:  https://doi.org/10.1007/978-3-031-14740-1_13
  2. Int J Mol Sci. 2022 Nov 23. pii: 14565. [Epub ahead of print]23(23):
    Role of Proteostasis Regulation in the Turnover of Stress Granules.
    Rirong Hu, Beituo Qian, Ang Li, Yanshan Fang.
      RNA-binding proteins (RBPs) and RNAs can form dynamic, liquid droplet-like cytoplasmic condensates, known as stress granules (SGs), in response to a variety of cellular stresses. This process is driven by liquid-liquid phase separation, mediated by multivalent interactions between RBPs and RNAs. The formation of SGs allows a temporary suspension of certain cellular activities such as translation of unnecessary proteins. Meanwhile, non-translating mRNAs may also be sequestered and stalled. Upon stress removal, SGs are disassembled to resume the suspended biological processes and restore the normal cell functions. Prolonged stress and disease-causal mutations in SG-associated RBPs can cause the formation of aberrant SGs and/or impair SG disassembly, consequently raising the risk of pathological protein aggregation. The machinery maintaining protein homeostasis (proteostasis) includes molecular chaperones and co-chaperones, the ubiquitin-proteasome system, autophagy, and other components, and participates in the regulation of SG metabolism. Recently, proteostasis has been identified as a major regulator of SG turnover. Here, we summarize new findings on the specific functions of the proteostasis machinery in regulating SG disassembly and clearance, discuss the pathological and clinical implications of SG turnover in neurodegenerative disorders, and point to the unresolved issues that warrant future exploration.
    Keywords:  G3BP; UPS; VCP; autophagy; chaperones; stress granule; ubiquitin
    DOI:  https://doi.org/10.3390/ijms232314565
  3. Int J Mol Sci. 2022 Dec 02. pii: 15186. [Epub ahead of print]23(23):
    Endoplasmic Reticulum Stress Signaling and Neuronal Cell Death.
    Adalberto Merighi, Laura Lossi.
      Besides protein processing, the endoplasmic reticulum (ER) has several other functions such as lipid synthesis, the transfer of molecules to other cellular compartments, and the regulation of Ca2+ homeostasis. Before leaving the organelle, proteins must be folded and post-translationally modified. Protein folding and revision require molecular chaperones and a favorable ER environment. When in stressful situations, ER luminal conditions or chaperone capacity are altered, and the cell activates signaling cascades to restore a favorable folding environment triggering the so-called unfolded protein response (UPR) that can lead to autophagy to preserve cell integrity. However, when the UPR is disrupted or insufficient, cell death occurs. This review examines the links between UPR signaling, cell-protective responses, and death following ER stress with a particular focus on those mechanisms that operate in neurons.
    Keywords:  apoptosis; autophagy; cerebellar granule cells; endoplasmic reticulum; endoplasmic reticulum stress; unfolded protein response
    DOI:  https://doi.org/10.3390/ijms232315186
  4. Subcell Biochem. 2023 ;101 247-291
    Co-chaperones of the Human Endoplasmic Reticulum: An Update.
    Armin Melnyk, Sven Lang, Mark Sicking, Richard Zimmermann, Martin Jung.
      In mammalian cells, the rough endoplasmic reticulum (ER) plays central roles in the biogenesis of extracellular plus organellar proteins and in various signal transduction pathways. For these reasons, the ER comprises molecular chaperones, which are involved in import, folding, assembly, export, plus degradation of polypeptides, and signal transduction components, such as calcium channels, calcium pumps, and UPR transducers plus adenine nucleotide carriers/exchangers in the ER membrane. The calcium- and ATP-dependent ER lumenal Hsp70, termed immunoglobulin heavy-chain-binding protein or BiP, is the central player in all these activities and involves up to nine different Hsp40-type co-chaperones, i.e., ER membrane integrated as well as ER lumenal J-domain proteins, termed ERj or ERdj proteins, two nucleotide exchange factors or NEFs (Grp170 and Sil1), and NEF-antagonists, such as MANF. Here we summarize the current knowledge on the ER-resident BiP/ERj chaperone network and focus on the interaction of BiP with the polypeptide-conducting and calcium-permeable Sec61 channel of the ER membrane as an example for BiP action and how its functional cycle is linked to ER protein import and various calcium-dependent signal transduction pathways.
    Keywords:  ATP/ADP exchange; Calcium-dependent signal transduction; Cellular calcium homeostasis; ER calcium leakage; ER energy homeostasis; ER protein import; ER-associated protein degradation; Human endoplasmic reticulum; J-domain proteins; Protein folding
    DOI:  https://doi.org/10.1007/978-3-031-14740-1_9
  5. Mol Biol Cell. 2023 Jan 01. 34(1): pe1
    Protein biosynthesis at the ER: finding the right accessories.
    Sichen Shao.
      More than 30% of eukaryotic proteins contain domains that must translocate across or integrate into the endoplasmic reticulum (ER) membrane. With few exceptions, protein translocation and transmembrane domain integration at the ER require the conserved Sec61 translocon. Decades of studies have established a clear mechanistic model for how the Sec61 translocon functions. The biosynthesis of distinct subsets of proteins at the ER also involves accessory factors that interact with the Sec61 translocon and translocating nascent proteins. However, assigning specific functions to many translocon accessory factors has been a persistent challenge in the field. This Perspective discusses recent insights into mechanisms that promote protein biosynthesis at the ER through accessory factors that directly regulate the Sec61 translocon or chaperone nascent proteins within the ER membrane. These translocon accessory factor functions, and more still to be discovered, are essential for producing a diverse and high-fidelity proteome at the ER.
    DOI:  https://doi.org/10.1091/mbc.E21-09-0451
  6. J Med Chem. 2022 Dec 14.
    Discovery and Development of a Selective Inhibitor of the ER Resident Chaperone Grp78.
    Andrew J Ambrose, Jared Sivinski, Christopher J Zerio, Xiaoyi Zhu, Jack Godek, Vlad K Kumirov, Teresa Coma Brujas, Joan Torra Garcia, Anandhan Annadurai, Cody J Schmidlin, Alyssa Werner, Taoda Shi, Reza Beheshti Zavareh, Luke Lairson, Donna D Zhang, Eli Chapman.
      A recent study illustrated that a fluorescence polarization assay can be used to identify substrate-competitive Hsp70 inhibitors that can be isoform-selective. Herein, we use that assay in a moderate-throughput screen and report the discovery of a druglike amino-acid-based inhibitor with reasonable specificity for the endoplasmic reticular Hsp70, Grp78. Using traditional medicinal chemistry approaches, the potency and selectivity were further optimized through structure-activity relationship (SAR) studies in parallel assays for six of the human Hsp70 isoforms. The top compounds were all tested against a panel of cancer cell lines and disappointingly showed little effect. The top-performing compound, 8, was retested using a series of endoplasmic reticulum (ER) stress-inducing agents and found to synergize with these agents. Finally, 8 was tested in a spheroid tumor model and found to be more potent than in two-dimensional models. The optimized Grp78 inhibitors are the first reported isoform-selective small-molecule-competitive inhibitors of an Hsp70-substrate interaction.
    DOI:  https://doi.org/10.1021/acs.jmedchem.2c01631
  7. Cell Tissue Res. 2022 Dec 16.
    CPNE1 regulates myogenesis through the PERK-eIF2α pathway mediated by endoplasmic reticulum stress.
    Lin Chen, Ling Pan, Yuexi Zeng, Xiaonan Zhu, Li You.
      Sarcopenia is characterized by a progressive reduction in muscle mass or muscle physiological function associated with aging, but the relevant molecular mechanisms are not clear. Here, we identify the role of the myogenesis modifier CPNE1 in sarcopenia. CPNE1 is upregulated in aged skeletal muscles and young skeletal muscle satellite cells with palmitate-induced atrophy. The overexpression of CPNE1 hinders proliferation and differentiation and increases muscle atrophy characteristics in young skeletal muscle-derived satellite cells. In addition, CPNE1 overexpression disrupts the balance of mitochondrial fusion and division and causes endoplasmic reticulum stress. We found that the effects of CPNE1 on mitochondrial function are dependent on the PERK/eIF2α/ATF4 pathway. The overexpression of CPNE1 in young muscles alters membrane lipid composition, reduces skeletal muscle fibrosis regeneration, and exercise capacity in mice. These effects were reversed by PERK inhibitor GSK2606414. Moreover, immunoprecipitation indicates that CPNE1 overexpression greatly increased the acetylation of PERK. Therefore, CPNE1 is an important modifier that drives mitochondrial homeostasis to regulate myogenic cell proliferation and differentiation via the PERK-eIF2α pathway, which could be a valuable target for age-related sarcopenia.
    Keywords:  CPNE1; Endoplasmic reticulum stress; PERK; Sarcopenia; eIF2α
    DOI:  https://doi.org/10.1007/s00441-022-03720-y
  8. Cell Mol Gastroenterol Hepatol. 2022 Dec 11. pii: S2352-345X(22)00252-1. [Epub ahead of print]
    Glycoprotein (GP)96 is essential for maintaining intestinal epithelial architecture by supporting its self-renewal capacity.
    Janine Häfliger, Marlene Schwarzfischer, Kirstin Atrott, Claudia Stanzel, Yasser Morsy, Marcin Wawrzyniak, Silvia Lang, Tomas Valenta, Konrad Basler, Gerhard Rogler, Michael Scharl, Marianne R Spalinger.
       BACKGROUND & AIMS: Glycoprotein (GP)96 is an endoplasmic reticulum (ER)-resident master chaperone for cell surface receptors including the Wnt co-receptors LRP5/6. Intestinal epithelial cells (IEC)-specific deletion of Gp96 is embryonically lethal. However, the role of GP96 in adult intestinal tissue and especially within the intestinal stem cell (ISC) niche has not been studied so far. Here, we investigated how GP96-loss interferes with intestinal homeostasis by compromising viability, proliferation and differentiation of IEC.
    METHODS: Tamoxifen was used to induce Cre-mediated deletion of Gp96 in GP96-VillincreERT2 mice and intestinal organoids. With H&E- and immunofluorescence staining we assessed alterations in intestinal morphology and the presence and localization of IEC-types. Real-time PCR and Western blot analysis were performed to explore the molecular mechanisms underlying the severe phenotype of Gp96 KO mice and organoids.
    RESULTS: IEC-specific deletion of Gp96 in adult mice resulted in a rapid degeneration of the stem cell niche, followed by a complete eradication of the epithelial layer and death within few days. These effects were due to severe defects in ISC renewal and premature ISC differentiation, which resulted from defective Wnt and Notch signaling. Furthermore, depletion of GP96 led to massive induction of ER stress. While effects on ISC renewal and adequate differentiation were partly reversed upon activation of Wnt/Notch signaling, viability could not be restored, indicating that reduced viability was mediated by other mechanisms.
    CONCLUSIONS: Our work demonstrates that GP96 plays a fundamental role in regulating ISC fate and epithelial regeneration and is therefore indispensable for maintaining intestinal epithelial homeostasis.
    Keywords:  ER stress; Intestinal stem cells; LRP6; Notch signaling; Wnt signaling
    DOI:  https://doi.org/10.1016/j.jcmgh.2022.12.004
  9. Stem Cell Rev Rep. 2022 Dec 17.
    Cell Surface Membrane Lipid Rafts as Potent Regulators of Stem Cell Proliferation, Differentiation, Trafficking and Metabolism.
    Mariusz Z Ratajczak.
      
    DOI:  https://doi.org/10.1007/s12015-022-10484-z
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