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      The Autophagy-Lysosomal Pathways and Their Emerging Roles in Modulating Proteostasis in Tumors

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          Abstract

          In normal physiological condition, the maintenance of cellular proteostasis is a prerequisite for cell growth, functioning, adapting to changing micro-environments, and responding to extracellular stress. Cellular proteostasis is maintained by specific proteostasis networks (PNs) to prevent protein misfolding, aggregating, and accumulating in subcellular compartments. Commonly, the PNs are composed of protein synthesis, molecular chaperones, endoplasmic reticulum (ER), unfolded protein response (UPR), stress response pathways (SRPs), secretions, ubiquitin proteasome system (UPS), and autophagy-lysosomal pathways (ALPs). Although great efforts have been made to explore the underlying detailed mechanisms of proteostasis, there are many questions remain to explore, especially in proteostasis regulated by the ALPs. Proteostasis out-off-balance is correlated with various human diseases such as diabetes, stroke, inflammation, hypertension, pulmonary fibrosis, and Alzheimer’s disease. Enhanced regulation of PNs is observed in tumors, thereby indicating that proteostasis may play a pivotal role in tumorigenesis and cancer development. Recently, inhibitors targeting the UPS have shown to be failed in solid tumor treatment. However, there is growing evidence showing that the ALPs play important roles in regulation of proteostasis alone or with a crosstalk with other PNs in tumors. In this review, we provide insights into the proteostatic process and how it is regulated by the ALPs, such as macroautophagy, aggrephagy, chaperone-mediated autophagy, microautophagy, as well as mitophagy during tumor development.

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          Most cited references109

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          Protein folding and misfolding.

          The manner in which a newly synthesized chain of amino acids transforms itself into a perfectly folded protein depends both on the intrinsic properties of the amino-acid sequence and on multiple contributing influences from the crowded cellular milieu. Folding and unfolding are crucial ways of regulating biological activity and targeting proteins to different cellular locations. Aggregation of misfolded proteins that escape the cellular quality-control mechanisms is a common feature of a wide range of highly debilitating and increasingly prevalent diseases.
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            Autophagy maintains stemness by preventing senescence.

            During ageing, muscle stem-cell regenerative function declines. At advanced geriatric age, this decline is maximal owing to transition from a normal quiescence into an irreversible senescence state. How satellite cells maintain quiescence and avoid senescence until advanced age remains unknown. Here we report that basal autophagy is essential to maintain the stem-cell quiescent state in mice. Failure of autophagy in physiologically aged satellite cells or genetic impairment of autophagy in young cells causes entry into senescence by loss of proteostasis, increased mitochondrial dysfunction and oxidative stress, resulting in a decline in the function and number of satellite cells. Re-establishment of autophagy reverses senescence and restores regenerative functions in geriatric satellite cells. As autophagy also declines in human geriatric satellite cells, our findings reveal autophagy to be a decisive stem-cell-fate regulator, with implications for fostering muscle regeneration in sarcopenia.
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              Mitochondria supply membranes for autophagosome biogenesis during starvation.

              Starvation-induced autophagosomes engulf cytosol and/or organelles and deliver them to lysosomes for degradation, thereby resupplying depleted nutrients. Despite advances in understanding the molecular basis of this process, the membrane origin of autophagosomes remains unclear. Here, we demonstrate that, in starved cells, the outer membrane of mitochondria participates in autophagosome biogenesis. The early autophagosomal marker, Atg5, transiently localizes to punctae on mitochondria, followed by the late autophagosomal marker, LC3. The tail-anchor of an outer mitochondrial membrane protein also labels autophagosomes and is sufficient to deliver another outer mitochondrial membrane protein, Fis1, to autophagosomes. The fluorescent lipid NBD-PS (converted to NBD-phosphotidylethanolamine in mitochondria) transfers from mitochondria to autophagosomes. Photobleaching reveals membranes of mitochondria and autophagosomes are transiently shared. Disruption of mitochondria/ER connections by mitofusin2 depletion dramatically impairs starvation-induced autophagy. Mitochondria thus play a central role in starvation-induced autophagy, contributing membrane to autophagosomes. Copyright (c) 2010 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Cells
                Cells
                cells
                Cells
                MDPI
                2073-4409
                20 December 2018
                January 2019
                : 8
                : 1
                : 4
                Affiliations
                [1 ]State Key Laboratory of Silkworm Genome Biology, Southwest University, Beibei, Chongqing 400716, China; zdong007@ 123456swu.edu.cn
                [2 ]Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Beibei, Chongqing 400716, China
                [3 ]Chongqing Engineering and Technology Research Center for Silk Biomaterials and Regenerative Medicine, Southwest University, Beibei, Chongqing 400716, China
                [4 ]Institute of Sericulture and Systems Biology, Southwest University, Beibei, Chongqing 400716, China
                Author notes
                [* ]Correspondence: hcui@ 123456swu.edu.cn or hongjuan.cui@ 123456gmail.com ; Tel.: +86-023-6825-1713
                Author information
                https://orcid.org/0000-0003-3108-0245
                https://orcid.org/0000-0003-1178-1570
                Article
                cells-08-00004
                10.3390/cells8010004
                6356230
                30577555
                53ad3d2c-4685-4f68-b841-2c747f77cc42
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 15 November 2018
                : 18 December 2018
                Categories
                Review

                autophagy-lysosomal pathways,proteostasis,protein misfolding,aggrephagy,tumors,aggregates,proteostasis networks,chaperones

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