bims-proarb Biomed News
on Proteostasis in aging and regenerative biology
Issue of 2021–11–07
eleven papers selected by
Rich Giadone, Harvard University
  1. BAX inhibitor-1 regulates autophagy by controlling the IRE1α branch of the unfolded protein response.
  2. Editorial: Dysregulated Protein Homeostasis in the Aging Organism.
  3. An update on the unfolded protein response in brain ischemia: Experimental evidence and therapeutic opportunities.
  4. Avoid shocking your hematopoietic stem cells to keep them young and growing.
  5. Natural compounds in the regulation of proteostatic pathways: An invincible artillery against stress, ageing, and diseases.
  6. Ubiquitination is essential for recovery of cellular activities after heat shock.
  7. Klotho as Potential Autophagy Regulator and Therapeutic Target.
  8. Caspase-mediated cleavage of miRNA processing proteins Drosha, DGCR8, Dicer, and TRBP2 in heat-shocked cells and its inhibition by HSP70 overexpression.
  9. TSC1 loss increases risk for tauopathy by inducing tau acetylation and preventing tau clearance via chaperone-mediated autophagy.
  10. [Proteome and Acetylome Profiling of Livers in C57BL/6J Male Mice during Normal Aging].
  11. Automating Aggregate Quantification in Caenorhabditis elegans.
  1. EMBO J. 2021 Nov 02. 40(21): e109149
    BAX inhibitor-1 regulates autophagy by controlling the IRE1α branch of the unfolded protein response.
    Karen Castillo, Diego Rojas-Rivera, Fernanda Lisbona, Benjamín Caballero, Melissa Nassif, Felipe A Court, Sebastian Schuck, Consuelo Ibar, Peter Walter, Jimena Sierralta, Alvaro Glavic, Claudio Hetz.
      
    DOI:  https://doi.org/10.15252/embj.2021109149
  2. Front Mol Biosci. 2021 ;8 788118
    Editorial: Dysregulated Protein Homeostasis in the Aging Organism.
    Thorsten Pfirrmann, Niki Chondrogianni, Heidi Olzscha, Aphrodite Vasilaki.
      
    Keywords:  autophagy; organismal aging; protein folding; protein modification; proteostasis; ubiquitin proteasome system
    DOI:  https://doi.org/10.3389/fmolb.2021.788118
  3. Neurochem Int. 2021 Oct 31. pii: S0197-0186(21)00264-3. [Epub ahead of print] 105218
    An update on the unfolded protein response in brain ischemia: Experimental evidence and therapeutic opportunities.
    Xuan Li, Wei Yang.
      After ischemic stroke or cardiac arrest, brain ischemia occurs. Currently, no pharmacologic intervention that targets cellular processes has proven effective in improving neurologic outcome in patients after brain ischemia. Recent experimental research has identified the crucial role of proteostasis in survival and recovery of cells after ischemia. In particular, the unfolded protein response (UPR), a key signaling pathway that safeguards cellular proteostasis, is emerging as a promising therapeutic target for brain ischemia. For some time, the UPR has been known to play a critical role in the pathophysiology of brain ischemia; however, only in the recent years has the field grown substantially, largely due to the extensive use of UPR-specific mouse genetic models and the rapidly expanding availability of pharmacologic tools that target the UPR. In this review, we provide a timely update on the progress in our understanding of the UPR in experimental brain ischemia, and discuss the therapeutic implications of targeting the UPR in ischemic stroke and cardiac arrest.
    Keywords:  Aging; Cardiac arrest; ER stress; Neuroprotection; Protein homeostasis; Stroke; UPR
    DOI:  https://doi.org/10.1016/j.neuint.2021.105218
  4. Cell Stem Cell. 2021 Nov 04. pii: S1934-5909(21)00419-7. [Epub ahead of print]28(11): 1887-1889
    Avoid shocking your hematopoietic stem cells to keep them young and growing.
    Maria-Eleni Lalioti, Jasmin Rettkowski, Nina Cabezas-Wallscheid.
      Expanding hematopoietic stem cells (HSCs) ex vivo has historically been a very challenging process. In this issue of Cell Stem Cell, Kruta et al. (2021) identify heat shock factor 1 (Hsf1) as a new target to maintain HSC fitness and protein homeostasis, not only in culture conditions but also upon aging.
    DOI:  https://doi.org/10.1016/j.stem.2021.10.007
  5. Acta Pharm Sin B. 2021 Oct;11(10): 2995-3014
    Natural compounds in the regulation of proteostatic pathways: An invincible artillery against stress, ageing, and diseases.
    Arun Upadhyay.
      Cells have different sets of molecules for performing an array of physiological functions. Nucleic acids have stored and carried the information throughout evolution, whereas proteins have been attributed to performing most of the cellular functions. To perform these functions, proteins need to have a unique conformation and a definite lifespan. These attributes are achieved by a highly coordinated protein quality control (PQC) system comprising chaperones to fold the proteins in a proper three-dimensional structure, ubiquitin-proteasome system for selective degradation of proteins, and autophagy for bulk clearance of cell debris. Many kinds of stresses and perturbations may lead to the weakening of these protective cellular machinery, leading to the unfolding and aggregation of cellular proteins and the occurrence of numerous pathological conditions. However, modulating the expression and functional efficiency of molecular chaperones, E3 ubiquitin ligases, and autophagic proteins may diminish cellular proteotoxic load and mitigate various pathological effects. Natural medicine and small molecule-based therapies have been well-documented for their effectiveness in modulating these pathways and reestablishing the lost proteostasis inside the cells to combat disease conditions. The present article summarizes various similar reports and highlights the importance of the molecules obtained from natural sources in disease therapeutics.
    Keywords:  17-AAG, 17-allylamino-geldanamycin; APC, anaphase-promoting complex; Ageing; Autophagy; BAG, BCL2-associated athanogene; CAP, chaperone-assisted proteasomal degradation; CASA, chaperone-assisted selective autophagy; CHIP, carboxy-terminus of HSC70 interacting protein; CMA, chaperone-mediated autophagy; Cancer; Chaperones; DUBs, deubiquitinases; Drug discovery; EGCG, epigallocatechin-3-gallate; ESCRT, endosomal sorting complexes required for transport; HECT, homologous to the E6-AP carboxyl terminus; HSC70, heat shock cognate 70; HSF1, heat shock factor 1; HSP, heat shock protein; KFERQ, lysine-phenylalanine-glutamate-arginine-glutamine; LAMP2a, lysosome-associated membrane protein 2a; LC3, light chain 3; NBR1, next to BRCA1 gene 1; Natural molecules; Neurodegeneration; PQC, protein quality control; Proteinopathies; Proteostasis; RING, really interesting new gene; UPS, ubiquitin–proteasome system; Ub, ubiquitin; Ubiquitin proteasome system
    DOI:  https://doi.org/10.1016/j.apsb.2021.01.006
  6. Science. 2021 Jun 25. 372(6549): eabc3593
    Ubiquitination is essential for recovery of cellular activities after heat shock.
    Brian A Maxwell, Youngdae Gwon, Ashutosh Mishra, Junmin Peng, Haruko Nakamura, Ke Zhang, Hong Joo Kim, J Paul Taylor.
      Tailoring stress responsesWhen faced with environmental stress, cells respond by shutting down cellular processes such as translation and nucleocytoplasmic transport. At the same time, cells preserve cytoplasmic messenger RNAs in structures known as stress granules, and many cellular proteins are modified by the covalent addition of ubiquitin, which has long been presumed to reflect degradation of stress-damaged proteins (see the Perspective by Dormann). Maxwell et al. show that cells generate distinct patterns of ubiquitination in response to different stressors. Rather than reflecting the degradation of stress-damaged proteins, this ubiquitination primes cells to dismantle stress granules and reinitiate normal cellular activities once the stress is removed. Gwon et al. show that persistent stress granules are degraded by autophagy, whereas short-lived granules undergo a process of disassembly that is autophagy independent. The mechanism of this disassembly depends on the initiating stress.Science, abc3593 and abf6548, this issue p. eabc3593 and p. eabf6548; see also abj2400, p. 1393.
    DOI:  https://doi.org/10.1126/science.abc3593
  7. Front Pharmacol. 2021 ;12 755366
    Klotho as Potential Autophagy Regulator and Therapeutic Target.
    Hongjing Zhou, Shiyun Pu, Houfeng Zhou, Yuanxin Guo.
      The protein Klotho can significantly delay aging, so it has attracted widespread attention. Abnormal downregulation of Klotho has been detected in several aging-related diseases, such as Alzheimer's disease, kidney injury, cancer, chronic obstructive pulmonary disease (COPD), vascular disease, muscular dystrophy and diabetes. Conversely, many exogenous and endogenous factors, several drugs, lifestyle changes and genetic manipulations were reported to exert therapeutic effects through increasing Klotho expression. In recent years, Klotho has been identified as a potential autophagy regulator. How Klotho may contribute to reversing the effects of aging and disease became clearer when it was linked to autophagy, the process in which eukaryotic cells clear away dysfunctional proteins and damaged organelles: the abovementioned diseases involve abnormal autophagy. Interestingly, growing evidence indicates that Klotho plays a dual role as inducer or inhibitor of autophagy in different physiological or pathological conditions through its influence on IGF-1/PI3K/Akt/mTOR signaling pathway, Beclin 1 expression and activity, as well as aldosterone level, which can help restore autophagy to beneficial levels. The present review examines the role of Klotho in regulating autophagy in Alzheimer's disease, kidney injury, cancer, COPD, vascular disease, muscular dystrophy and diabetes. Targeting Klotho may provide a new perspective for preventing and treating aging-related diseases.
    Keywords:  alzhaimer’s disease; autophagy; cancer; chronic obstructive pulmonary disease; kidney injury; klotho; muscular dystrophy; vascular disease
    DOI:  https://doi.org/10.3389/fphar.2021.755366
  8. Cell Stress Chaperones. 2021 Oct 31.
    Caspase-mediated cleavage of miRNA processing proteins Drosha, DGCR8, Dicer, and TRBP2 in heat-shocked cells and its inhibition by HSP70 overexpression.
    Lina Y Abou Zeid, Shanmugapriya Shanmugapriya, Rebecca L Rumney, Dick D Mosser.
      Cells respond to stress through adaptive mechanisms that limit cellular damage and prevent cell death. MicroRNAs act as regulators of stress responses and stress can impact the functioning of miRNA biogenesis pathways. We were interested in the effect that severe proteotoxic stress capable of inducing apoptosis may have on miRNA biogenesis and the impact of the molecular chaperone protein HSP70 under these conditions. We found that the miRNA processing enzymes Drosha and Dicer and their accessory proteins DGCR8 and TRBP2 are cleaved by caspases in apoptotic cells. Overexpression of HSP70 prevented caspase activation and the degradation of these processing proteins. Caspase cleavage of TRBP2 was mapped to amino acid 234 which separates the two dsRNA-binding domains from the C-terminal Dicer interacting domain. Overexpression of TRBP2 was found to increase miRNA maturation, while expression of either of the fragments generated by caspase cleavage impaired maturation. These results indicate that inactivation of miRNA biogenesis is a critical feature of apoptosis and that cleavage of TRBP2, rather than simply a loss of function, serves to create positive acting inhibitors of pre-miRNA maturation.
    Keywords:  Apoptosis; HSP70; Heat shock proteins; Hyperthermia; MicroRNA; TRBP
    DOI:  https://doi.org/10.1007/s12192-021-01242-0
  9. Sci Adv. 2021 Nov 05. 7(45): eabg3897
    TSC1 loss increases risk for tauopathy by inducing tau acetylation and preventing tau clearance via chaperone-mediated autophagy.
    Carolina Alquezar, Kathleen M Schoch, Ethan G Geier, Eliana Marisa Ramos, Aurora Scrivo, Kathy H Li, Andrea R Argouarch, Elisabeth E Mlynarski, Beth Dombroski, Michael DeTure, Dennis W Dickson, Jennifer S Yokoyama, Ana M Cuervo, Alma L Burlingame, Gerard D Schellenberg, Timothy M Miller, Bruce L Miller, Aimee W Kao.
      [Figure: see text].
    DOI:  https://doi.org/10.1126/sciadv.abg3897
  10. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2021 Oct;43(5): 696-705
    [Proteome and Acetylome Profiling of Livers in C57BL/6J Male Mice during Normal Aging].
    Jiang-Feng Liu, Ye-Hong Yang, Yue Wu, Jun-Tao Yang.
      Objective To obtain the proteome and acetylome profiles of livers in mice during normal aging.Methods We applied tandem mass tag labeling and liquid chromatography tandem mass spectrometry and achieved proteome and acetylome data in C57BL/6J male mice aged 2 and 18 months under physiological conditions.Results A total of 4712 proteins were quantified by proteome profiling,and 4818 acetylated sites in 1367 proteins by acetylome profiling.The proteome and acetylome revealed moderate differences in the livers of young and old mice.There were 195 differentially expressed proteins in the proteome and 113 differentially expressed acetylated sites corresponding to 76 proteins in the acetylome.Functional enrichment analysis for the proteome showed that aging-associated upregulated proteins were mainly involved in fatty acid metabolism,epoxygenase P450 pathway,drug catabolic process,organic hydroxy compound metabolic process,and arachidonic acid metabolic process,while the downregulated proteins were related to regulation of gene silencing,nucleosome assembly,protein heterotetramerization,response to interferon,protein-DNA complex assembly and other processes.For the acetylome,the proteins with aging-associated upregulated acetylated sites mainly participated in cofactor metabolism,small molecule catabolic process,ribose phosphate metabolic process,ribonucleotide metabolic process,and purine-containing compound metabolic process,while the proteins with downregulated acetylated sites were associated with sulfur compound metabolic process,response to unfolded protein,and amino acid metabolic process.Conclusion We profiled the proteome and acetylome of livers in mice during normal aging and generated datasets for further research on aging.
    Keywords:  acetylation; aging; liver; mice; proteome
    DOI:  https://doi.org/10.3881/j.issn.1000-503X.13954
  11. J Vis Exp. 2021 Oct 14.
    Automating Aggregate Quantification in Caenorhabditis elegans.
    Alfonso S Vaziriyan-Sani, Robert D Handy, Alyssa C Walker, Carol Navya Pagolu, Samantha M Enslow, Daniel M Czyż.
      A rise in the prevalence of neurodegenerative protein conformational diseases (PCDs) has fostered a great interest in this subject over the years. This increased attention has called for the diversification and improvement of animal models capable of reproducing disease phenotypes observed in humans with PCDs. Though murine models have proven invaluable, they are expensive and are associated with laborious, low-throughput methods. Use of the Caenorhabditis elegans nematode model to study PCDs has been justified by its relative ease of maintenance, low cost, and rapid generation time, which allow for high-throughput applications. Additionally, high conservation between the C. elegans and human genomes makes this model an invaluable discovery tool. Nematodes that express fluorescently tagged tissue-specific polyglutamine (polyQ) tracts exhibit age- and polyQ length-dependent aggregation characterized by fluorescent foci. Such reporters are often employed as proxies to monitor changes in proteostasis across tissues. Manual aggregate quantification is time-consuming, limiting experimental throughput. Furthermore, manual foci quantification can introduce bias, as aggregate identification can be highly subjective. Herein, a protocol consisting of worm culturing, image acquisition, and data processing was standardized to support high-throughput aggregate quantification using C. elegans that express intestine-specific polyQ. By implementing a C. elegans-based image processing pipeline using CellProfiler, an image analysis software, this method has been optimized to separate and identify individual worms and enumerate their respective aggregates. Though the concept of automation is not entirely unique, the need to standardize such procedures for reproducibility, elimination of bias from manual counting, and increase throughput is high. It is anticipated that these methods can drastically simplify the screening process of large bacterial, genomic, or drug libraries using the C. elegans model.
    DOI:  https://doi.org/10.3791/62997
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