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      Regulation of cell-non-autonomous proteostasis in metazoans

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          Abstract

          Cells have developed robust adaptation mechanisms to survive environmental conditions that challenge the integrity of their proteome and ensure cellular viability. These are stress signalling pathways that integrate extracellular signals with the ability to detect and efficiently respond to protein-folding perturbations within the cell. Within the context of an organism, the cell-autonomous effects of these signalling mechanisms are superimposed by cell-non-autonomous stress signalling pathways that allow co-ordination of stress responses across tissues. These transcellular stress signalling pathways orchestrate and maintain the cellular proteome at an organismal level. This article focuses on mechanisms in both invertebrate and vertebrate organisms that activate stress responses in a cell-non-autonomous manner. We discuss emerging insights and provide specific examples on how components of the cell-non-autonomous proteostasis network are used in cancer and protein-folding diseases to drive disease progression across tissues.

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          Most cited references22

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          Regulation of aging and age-related disease by DAF-16 and heat-shock factor.

          A.-L. Hsu (2003)
          The Caenorhabditis elegans transcription factor HSF-1, which regulates the heat-shock response, also influences aging. Reducing hsf-1 activity accelerates tissue aging and shortens life-span, and we show that hsf-1 overexpression extends lifespan. We find that HSF-1, like the transcription factor DAF-16, is required for daf-2-insulin/IGF-1 receptor mutations to extend life-span. Our findings suggest this is because HSF-1 and DAF-16 together activate expression of specific genes, including genes encoding small heat-shock proteins, which in turn promote longevity. The small heat-shock proteins also delay the onset of polyglutamine-expansion protein aggregation, suggesting that these proteins couple the normal aging process to this type of age-related disease.
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            Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging.

            The long-term health of the cell is inextricably linked to protein quality control. Under optimal conditions this is accomplished by protein homeostasis, a highly complex network of molecular interactions that balances protein biosynthesis, folding, translocation, assembly/disassembly, and clearance. This review will examine the consequences of an imbalance in homeostasis on the flux of misfolded proteins that, if unattended, can result in severe molecular damage to the cell. Adaptation and survival requires the ability to sense damaged proteins and to coordinate the activities of protective stress response pathways and chaperone networks. Yet, despite the abundance and apparent capacity of chaperones and other components of homeostasis to restore folding equilibrium, the cell appears poorly adapted for chronic proteotoxic stress when conformationally challenged aggregation-prone proteins are expressed in cancer, metabolic disease, and neurodegenerative disease. The decline in biosynthetic and repair activities that compromises the integrity of the proteome is influenced strongly by genes that control aging, thus linking stress and protein homeostasis with the health and life span of the organism.
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              Collapse of proteostasis represents an early molecular event in Caenorhabditis elegans aging.

              Protein damage contributes prominently to cellular aging. To address whether this occurs at a specific period during aging or accumulates gradually, we monitored the biochemical, cellular, and physiological properties of folding sensors expressed in different tissues of C. elegans. We observed the age-dependent misfolding and loss of function of diverse proteins harboring temperature-sensitive missense mutations in all somatic tissues at the permissive condition. This widespread failure in proteostasis occurs rapidly at an early stage of adulthood, and coincides with a severely reduced activation of the cytoprotective heat shock response and the unfolded protein response. Enhancing stress responsive factors HSF-1 or DAF-16 suppresses misfolding of these metastable folding sensors and restores the ability of the cell to maintain a functional proteome. This suggests that a compromise in the regulation of proteostatic stress responses occurs early in adulthood and tips the balance between the load of damaged proteins and the proteostasis machinery. We propose that the collapse of proteostasis represents an early molecular event of aging that amplifies protein damage in age-associated diseases of protein conformation.
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                Author and article information

                Journal
                Essays Biochem
                Essays Biochem
                ppebio
                BSE
                BSE
                Essays in Biochemistry
                Portland Press Limited
                0071-1365
                1744-1358
                15 October 2016
                15 October 2016
                : 60
                : 2 , Proteostasis ( displayID: 2 )
                : 133-142
                Affiliations
                [ 1 ]School of Molecular and Cell Biology and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, U.K.
                Author notes
                [* ] Correspondence: Patricija van Oosten-Hawle (email p.vanoosten-hawle@ 123456leeds.ac.uk ).
                Article
                EBC20160006
                10.1042/EBC20160006
                5065704
                27744329
                4a2b0fc4-1287-4dd7-9297-f2e6db32584e
                © 2016 The Author(s)

                This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution Licence 4.0 (CC BY).

                History
                : 14 January 2016
                : 21 April 2016
                : 28 April 2016
                Page count
                Figures: 3, References: 41, Pages: 10
                Categories
                10
                13

                cancer,cell-non-autonomous,heat-shock response,protein-misfolding diseases,proteostasis,stress responses,systemic proteostasis,transcellular chaperone signalling,unfolded protein response

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