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      p62 links the autophagy pathway and the ubiqutin–proteasome system upon ubiquitinated protein degradation

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          Abstract

          The ubiquitin–proteasome system (UPS) and autophagy are two distinct and interacting proteolytic systems. They play critical roles in cell survival under normal conditions and during stress. An increasing body of evidence indicates that ubiquitinated cargoes are important markers of degradation. p62, a classical receptor of autophagy, is a multifunctional protein located throughout the cell and involved in many signal transduction pathways, including the Keap1–Nrf2 pathway. It is involved in the proteasomal degradation of ubiquitinated proteins. When the cellular p62 level is manipulated, the quantity and location pattern of ubiquitinated proteins change with a considerable impact on cell survival. Altered p62 levels can even lead to some diseases. The proteotoxic stress imposed by proteasome inhibition can activate autophagy through p62 phosphorylation. A deficiency in autophagy may compromise the ubiquitin–proteasome system, since overabundant p62 delays delivery of the proteasomal substrate to the proteasome despite proteasomal catalytic activity being unchanged. In addition, p62 and the proteasome can modulate the activity of HDAC6 deacetylase, thus influencing the autophagic degradation.

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          Autophagosome formation: core machinery and adaptations.

          Eukaryotic cells employ autophagy to degrade damaged or obsolete organelles and proteins. Central to this process is the formation of autophagosomes, double-membrane vesicles responsible for delivering cytoplasmic material to lysosomes. In the past decade many autophagy-related genes, ATG, have been identified that are required for selective and/or nonselective autophagic functions. In all types of autophagy, a core molecular machinery has a critical role in forming sequestering vesicles, the autophagosome, which is the hallmark morphological feature of this dynamic process. Additional components allow autophagy to adapt to the changing needs of the cell.
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            Aggresomes: A Cellular Response to Misfolded Proteins

            Intracellular deposition of misfolded protein aggregates into ubiquitin-rich cytoplasmic inclusions is linked to the pathogenesis of many diseases. Why these aggregates form despite the existence of cellular machinery to recognize and degrade misfolded protein and how they are delivered to cytoplasmic inclusions are not known. We have investigated the intracellular fate of cystic fibrosis transmembrane conductance regulator (CFTR), an inefficiently folded integral membrane protein which is degraded by the cytoplasmic ubiquitin-proteasome pathway. Overexpression or inhibition of proteasome activity in transfected human embryonic kidney or Chinese hamster ovary cells led to the accumulation of stable, high molecular weight, detergent-insoluble, multiubiquitinated forms of CFTR. Using immunofluorescence and transmission electron microscopy with immunogold labeling, we demonstrate that undegraded CFTR molecules accumulate at a distinct pericentriolar structure which we have termed the aggresome. Aggresome formation is accompanied by redistribution of the intermediate filament protein vimentin to form a cage surrounding a pericentriolar core of aggregated, ubiquitinated protein. Disruption of microtubules blocks the formation of aggresomes. Similarly, inhibition of proteasome function also prevented the degradation of unassembled presenilin-1 molecules leading to their aggregation and deposition in aggresomes. These data lead us to propose that aggresome formation is a general response of cells which occurs when the capacity of the proteasome is exceeded by the production of aggregation-prone misfolded proteins.
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              A role for ubiquitin in selective autophagy.

              Ubiquitination is the hallmark of protein degradation by the 26S proteasome. However, the proteasome is limited in its capacity to degrade oligomeric and aggregated proteins. Removal of harmful protein aggregates is mediated by autophagy, a mechanism by which the cell sequesters cytosolic cargo and delivers it for degradation by the lysosome. Identification of autophagy receptors, such as p62/SQSTM1 and NBR1, which simultaneously bind both ubiquitin and autophagy-specific ubiquitin-like modifiers, LC3/GABARAP, has provided a molecular link between ubiquitination and autophagy. This review explores the hypothesis that ubiquitin represents a selective degradation signal suitable for targeting various types of cargo, ranging from protein aggregates to membrane-bound organelles and microbes.
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                Author and article information

                Contributors
                yelin_gdmu@126.com
                86-759-2387583 , hf-liu@263.net
                Journal
                Cell Mol Biol Lett
                Cell. Mol. Biol. Lett
                Cellular & Molecular Biology Letters
                BioMed Central (London )
                1425-8153
                1689-1392
                13 December 2016
                13 December 2016
                2016
                : 21
                : 29
                Affiliations
                [1 ]GRID grid.410560.6, ISNI 0000000417603078, The Institute of Nephrology, , Guangdong Medical University, ; Zhanjiang, Guangdong 524001 China
                [2 ]GRID grid.412073.3, Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, , Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, ; Beijing, 100700 China
                Article
                31
                10.1186/s11658-016-0031-z
                5415757
                28536631
                2a505d35-faf2-4bd2-9a81-5cacb45b98f2
                © The Author(s) 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 4 December 2016
                : 7 December 2016
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81570656
                Award ID: 81470959
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100003453, Natural Science Foundation of Guangdong Province;
                Award ID: 2014A030313540
                Award Recipient :
                Funded by: Medical Scientific Research Foundation of Guangdong Province
                Award ID: A2015138
                Award ID: A2014480
                Award Recipient :
                Funded by: The Administration of Traditional Chinese Meddicine of Guangdong Province
                Award ID: 20141153
                Award Recipient :
                Categories
                Mini Review
                Custom metadata
                © The Author(s) 2016

                p62,autophagy,ubiquitin–proteasome system (ups),ubiquitinated protein,aggresome,proteostasis,p62 phosphorylation,keap1–nrf2 pathway,histone deacetylase 6 (hdac6),mechanistic target of rapamycin complex 1 (mtorc1)

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