scispace - formally typeset
Search or ask a question
Journal ArticleDOI

Shaping proteostasis at the cellular, tissue, and organismal level.

01 May 2017-Journal of Cell Biology (Rockefeller University Press)-Vol. 216, Iss: 5, pp 1231-1241
TL;DR: 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.
Abstract: The proteostasis network (PN) regulates protein synthesis, folding, transport, and degradation to maintain proteome integrity and limit the accumulation of protein aggregates, a hallmark of aging and degenerative diseases. In multicellular organisms, the PN is regulated at the cellular, tissue, and systemic level to ensure organismal health and longevity. Here we review these three layers of PN regulation and examine how they collectively maintain cellular homeostasis, achieve cell type-specific proteomes, and coordinate proteostasis across tissues. A precise understanding of these layers of control has important implications for organismal health and could offer new therapeutic approaches for neurodegenerative diseases and other chronic disorders related to PN dysfunction.

Content maybe subject to copyright    Report

Citations
More filters
Journal ArticleDOI
TL;DR: The possibilities of pharmacological augmentation of the capacity of proteostasis networks hold great promise for delaying the onset of age-related pathologies associated with proteome deterioration and for extending healthspan.
Abstract: Ageing is a major risk factor for the development of many diseases, prominently including neurodegenerative disorders such as Alzheimer disease and Parkinson disease. A hallmark of many age-related diseases is the dysfunction in protein homeostasis (proteostasis), leading to the accumulation of protein aggregates. In healthy cells, a complex proteostasis network, comprising molecular chaperones and proteolytic machineries and their regulators, operates to ensure the maintenance of proteostasis. These factors coordinate protein synthesis with polypeptide folding, the conservation of protein conformation and protein degradation. However, sustaining proteome balance is a challenging task in the face of various external and endogenous stresses that accumulate during ageing. These stresses lead to the decline of proteostasis network capacity and proteome integrity. The resulting accumulation of misfolded and aggregated proteins affects, in particular, postmitotic cell types such as neurons, manifesting in disease. Recent analyses of proteome-wide changes that occur during ageing inform strategies to improve proteostasis. The possibilities of pharmacological augmentation of the capacity of proteostasis networks hold great promise for delaying the onset of age-related pathologies associated with proteome deterioration and for extending healthspan. Misfolded proteins have a high propensity to form potentially toxic aggregates. Cells employ a complex network of processes, involving chaperones and proteolytic machineries that ensure proper protein folding and remodel or degrade misfolded species and aggregates. This proteostasis network declines with age, which can be linked to human degenerative diseases.

705 citations

Journal ArticleDOI
TL;DR: Klaips et al. outline the pathways and molecular mechanisms of cellular protein homeostasis, or protestasis, and discuss how a decline in proteostasis during aging contributes to disease.
Abstract: Ensuring cellular protein homeostasis, or proteostasis, requires precise control of protein synthesis, folding, conformational maintenance, and degradation. A complex and adaptive proteostasis network coordinates these processes with molecular chaperones of different classes and their regulators functioning as major players. This network serves to ensure that cells have the proteins they need while minimizing misfolding or aggregation events that are hallmarks of age-associated proteinopathies, including neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. It is now clear that the capacity of cells to maintain proteostasis undergoes a decline during aging, rendering the organism susceptible to these pathologies. Here we discuss the major proteostasis pathways in light of recent research suggesting that their age-dependent failure can both contribute to and result from disease. We consider different strategies to modulate proteostasis capacity, which may help develop urgently needed therapies for neurodegeneration and other age-dependent pathologies.

532 citations


Cites background from "Shaping proteostasis at the cellula..."

  • ...In metazoans the stress-response pathways additionally underlie cell nonautonomous regulation, allowing coordination within and between tissues and organs (Taylor et al., 2014; Sala et al., 2017)....

    [...]

  • ...…(Uhlén et al., 2015), tissue-specific proteomes and regulatory programs imply that there must be a marked heterogeneity in aspects of proteostasis across diverse cell types, suggesting the existence of tissue-specific PNs (Sala et al., 2017) with differing contributions of the three branches....

    [...]

  • ...However, in metazoans (Guisbert et al., 2013), especially in complex mammalian systems (Uhlén et al., 2015), tissue-specific proteomes and regulatory programs imply that there must be a marked heterogeneity in aspects of proteostasis across diverse cell types, suggesting the existence of tissue-specific PNs (Sala et al., 2017) with differing contributions of the three branches....

    [...]

  • ..., 2015), tissue-specific proteomes and regulatory programs imply that there must be a marked heterogeneity in aspects of proteostasis across diverse cell types, suggesting the existence of tissue-specific PNs (Sala et al., 2017) with differing contributions of the three branches....

    [...]

  • ...The repertoire of human chaperones (the “chaperome”) contains ∼330 members of several functionally distinct gene families, which cater to diverse substrate clients (Brehme et al., 2014; Sala et al., 2017; Fig....

    [...]

Journal ArticleDOI
TL;DR: It is pointed out that longitudinal studies with a life course approach are needed to gain further mechanistic insight on the processes that lead to functional decline with aging, and the role played by inflammation and environmental challenges.

238 citations

Journal ArticleDOI
03 Jan 2018-Neuron
TL;DR: It is hypothesized that firing instability and impaired synaptic plasticity at early AD stages trigger a vicious cycle, leading to dysregulation of the whole IHN, and represents the major driving force of the transition from early memory impairments to neurodegeneration.

169 citations


Cites background from "Shaping proteostasis at the cellula..."

  • ...In addition to accumulated evidence regarding activity-dependent regulation of proteostasis in mammals, studies in model organisms provide fundamental insights into the mechanisms of proteostasis at different scales: cellular, tissue, and systemic (Sala et al., 2017)....

    [...]

  • ...The proteostasis network regulates protein synthesis, folding, transport, and degradation to maintain proteome integrity and limit the accumulation of protein aggregates (Balch et al., 2008; Sala et al., 2017)....

    [...]

Journal ArticleDOI
TL;DR: The capacity and limitations of the PN in maintaining proteome integrity in the face of proteotoxic stresses, such as aggregate formation in neurodegenerative diseases are discussed.
Abstract: Cells invest in an extensive network of factors to maintain protein homeostasis (proteostasis) and prevent the accumulation of potentially toxic protein aggregates. This proteostasis network (PN) comprises the machineries for the biogenesis, folding, conformational maintenance, and degradation of proteins with molecular chaperones as central coordinators. Here, we review recent progress in understanding the modular architecture of the PN in mammalian cells and how it is modified during cell differentiation. We discuss the capacity and limitations of the PN in maintaining proteome integrity in the face of proteotoxic stresses, such as aggregate formation in neurodegenerative diseases. Finally, we outline various pharmacological interventions to ameliorate proteostasis imbalance.

111 citations


Cites background from "Shaping proteostasis at the cellula..."

  • ...Moreover, in most cases specific cell types and tissues are exclusively or preferentially affected (Fu et al. 2018), suggesting an underlying heterogeneity between cell types in proteostasis capacity and the ability to respond to proteotoxic stress (Sala et al. 2017)....

    [...]

References
More filters
Journal ArticleDOI
23 Jan 2015-Science
TL;DR: In this paper, a map of the human tissue proteome based on an integrated omics approach that involves quantitative transcriptomics at the tissue and organ level, combined with tissue microarray-based immunohistochemistry, to achieve spatial localization of proteins down to the single-cell level.
Abstract: Resolving the molecular details of proteome variation in the different tissues and organs of the human body will greatly increase our knowledge of human biology and disease. Here, we present a map of the human tissue proteome based on an integrated omics approach that involves quantitative transcriptomics at the tissue and organ level, combined with tissue microarray-based immunohistochemistry, to achieve spatial localization of proteins down to the single-cell level. Our tissue-based analysis detected more than 90% of the putative protein-coding genes. We used this approach to explore the human secretome, the membrane proteome, the druggable proteome, the cancer proteome, and the metabolic functions in 32 different tissues and organs. All the data are integrated in an interactive Web-based database that allows exploration of individual proteins, as well as navigation of global expression patterns, in all major tissues and organs in the human body.

9,745 citations

Journal ArticleDOI
TL;DR: This review discusses recent information on functions and mechanisms of the ubiquitin system and focuses on what the authors know, and would like to know, about the mode of action of ubi...
Abstract: The selective degradation of many short-lived proteins in eukaryotic cells is carried out by the ubiquitin system. In this pathway, proteins are targeted for degradation by covalent ligation to ubiquitin, a highly conserved small protein. Ubiquitin-mediated degradation of regulatory proteins plays important roles in the control of numerous processes, including cell-cycle progression, signal transduction, transcriptional regulation, receptor down-regulation, and endocytosis. The ubiquitin system has been implicated in the immune response, development, and programmed cell death. Abnormalities in ubiquitin-mediated processes have been shown to cause pathological conditions, including malignant transformation. In this review we discuss recent information on functions and mechanisms of the ubiquitin system. Since the selectivity of protein degradation is determined mainly at the stage of ligation to ubiquitin, special attention is focused on what we know, and would like to know, about the mode of action of ubiquitin-protein ligation systems and about signals in proteins recognized by these systems.

7,888 citations

Journal ArticleDOI
25 Nov 2011-Science
TL;DR: The vast majority of proteins that a cell secretes or displays on its surface first enter the endoplasmic reticulum, where they fold and assemble, and only properly assembled proteins advance from the ER to the cell surface.
Abstract: The vast majority of proteins that a cell secretes or displays on its surface first enter the endoplasmic reticulum (ER), where they fold and assemble. Only properly assembled proteins advance from the ER to the cell surface. To ascertain fidelity in protein folding, cells regulate the protein-folding capacity in the ER according to need. The ER responds to the burden of unfolded proteins in its lumen (ER stress) by activating intracellular signal transduction pathways, collectively termed the unfolded protein response (UPR). Together, at least three mechanistically distinct branches of the UPR regulate the expression of numerous genes that maintain homeostasis in the ER or induce apoptosis if ER stress remains unmitigated. Recent advances shed light on mechanistic complexities and on the role of the UPR in numerous diseases.

4,468 citations


"Shaping proteostasis at the cellula..." refers background in this paper

  • ...Both XBP1 and ATF6 induce prosurvival pathways that up-regulate genes involved in protein folding, ER-associated protein degradation, and lipid metabolism (Walter and Ron, 2011)....

    [...]

Journal ArticleDOI
TL;DR: It is demonstrated that Nrf2 is essential for the transcriptional induction of phase II enzymes and the presence of a coordinate transcriptional regulatory mechanism for phase II enzyme genes and the nrf2-deficient mice may prove to be a very useful model for the in vivo analysis of chemical carcinogenesis and resistance to anti-cancer drugs.

3,557 citations


"Shaping proteostasis at the cellula..." refers background in this paper

  • ...Enhanced proteostasis and extended lifespan in animals devoid of a germline rely on multiple transcription factors, including DAF16, PHA4, and SKN1, in addition to HSF1 (Lin et al., 2001; Lapierre et al., 2011; Steinbaugh et al., 2015)....

    [...]

  • ...elegans these functions are performed by SKN1 (Itoh et al., 1997; An and Blackwell, 2003; Radhakrishnan et al., 2010)....

    [...]

  • ...The OxR has two branches, which are mediated by the stress-responsive transcription factors NRF1/NFE2L1 and NRF2/NFE2L2 in mammals, whereas in C. elegans these functions are performed by SKN1 (Itoh et al., 1997; An and Blackwell, 2003; Radhakrishnan et al., 2010)....

    [...]

  • ...Conversely, key UPRER signaling factors are involved in the activation of SKN1 during oxidative stress....

    [...]

  • ...Notably, these two SKN1-mediated responses as part of the UPRER and OxR have distinct but overlapping targets (Glover-Cutter et al., 2013)....

    [...]

Journal ArticleDOI
23 Nov 2001-Science
TL;DR: Two genes encode ubiquitin ligases that are potential drug targets for the treatment of muscle atrophy, and mice deficient in either MAFbx orMuRF1 were found to be resistant to atrophy.
Abstract: Skeletal muscle adapts to decreases in activity and load by undergoing atrophy. To identify candidate molecular mediators of muscle atrophy, we performed transcript profiling. Although many genes were up-regulated in a single rat model of atrophy, only a small subset was universal in all atrophy models. Two of these genes encode ubiquitin ligases: Muscle RING Finger 1 (MuRF1), and a gene we designate Muscle Atrophy F-box (MAFbx), the latter being a member of the SCF family of E3 ubiquitin ligases. Overexpression of MAFbx in myotubes produced atrophy, whereas mice deficient in either MAFbx or MuRF1 were found to be resistant to atrophy. These proteins are potential drug targets for the treatment of muscle atrophy.

3,174 citations


"Shaping proteostasis at the cellula..." refers background in this paper

  • ...The muscle-specific ubiquitin ligases MAFbx/ atrogin-1 and MuRF family members are induced and mediate breakdown of various muscle proteins during atrophic conditions, further demonstrating the need for specific PN activities in this tissue (Bodine et al., 2001; Gomes et al., 2001)....

    [...]