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      Emerging role and therapeutic application of exosome in hepatitis virus infection and associated diseases

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          Abstract

          Hepatitis viruses are chief pathogens of hepatitis and end-stage liver diseases. Their replication and related pathogenic process highly rely on the host micro-environment and multiple cellular elements, including exosomes. Representing with a sort of cell-derived vesicle structure, exosomes were considered to be dispensable cellular components, even wastes. Along with advancing investigation, a specific profile of exosome in driving hepatitis viruses’ infection and hepatic disease progression is revealed. Exosomes greatly affect the pathogenesis of hepatitis viruses by mediating their replication and modulating the host immune responses. The characteristics of host exosomes are markedly changed after infection with hepatitis viruses. Exosomes released from hepatitis virus-infected cells can carry viral nucleic or protein components, thereby acting as an effective subterfuge for hepatitis viruses by participating in viral transportation and immune escape. On the contrary, immune cell-derived exosomes contribute toward the innate antiviral immune defense and virus eradication. There is growing evidence supporting the application of exosomal biomarkers for predicting disease progress or therapeutic outcome, while exosomal nanoshuttles are regarded as promising therapeutic options based on their delivery properties and immune compatibility. In this review, we summarize the biogenesis and secretion mechanism of exosomes, review the recent findings pertaining to the role of exosomes in the interplay between hepatitis viruses and innate immune responses, and conclude their potential in further therapeutic application.

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          Most cited references139

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          Biogenesis and secretion of exosomes.

          Although observed for several decades, the release of membrane-enclosed vesicles by cells into their surrounding environment has been the subject of increasing interest in the past few years, which led to the creation, in 2012, of a scientific society dedicated to the subject: the International Society for Extracellular Vesicles. Convincing evidence that vesicles allow exchange of complex information fuelled this rise in interest. But it has also become clear that different types of secreted vesicles co-exist, with different intracellular origins and modes of formation, and thus probably different compositions and functions. Exosomes are one sub-type of secreted vesicles. They form inside eukaryotic cells in multivesicular compartments, and are secreted when these compartments fuse with the plasma membrane. Interestingly, different families of molecules have been shown to allow intracellular formation of exosomes and their subsequent secretion, which suggests that even among exosomes different sub-types exist. Copyright © 2014 Elsevier Ltd. All rights reserved.
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            Ceramide triggers budding of exosome vesicles into multivesicular endosomes.

            Intraluminal vesicles of multivesicular endosomes are either sorted for cargo degradation into lysosomes or secreted as exosomes into the extracellular milieu. The mechanisms underlying the sorting of membrane into the different populations of intraluminal vesicles are unknown. Here, we find that cargo is segregated into distinct subdomains on the endosomal membrane and that the transfer of exosome-associated domains into the lumen of the endosome did not depend on the function of the ESCRT (endosomal sorting complex required for transport) machinery, but required the sphingolipid ceramide. Purified exosomes were enriched in ceramide, and the release of exosomes was reduced after the inhibition of neutral sphingomyelinases. These results establish a pathway in intraendosomal membrane transport and exosome formation.
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              The ESCRT machinery in endosomal sorting of ubiquitylated membrane proteins.

              Selective trafficking of membrane proteins to lysosomes for destruction is required for proper cell signalling and metabolism. Ubiquitylation aids this process by specifying which proteins should be transported to the lysosome lumen by the multivesicular endosome pathway. The endosomal sorting complex required for transport (ESCRT) machinery sorts cargo labelled with ubiquitin into invaginations of endosome membranes. Then, through a highly conserved mechanism also used in cytokinesis and viral budding, it mediates the breaking off of the cargo-containing intraluminal vesicles from the perimeter membrane. The involvement of the ESCRT machinery in suppressing diseases such as cancer, neurodegeneration and infections underscores its importance to the cell.
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                Author and article information

                Contributors
                htang6198@hotmail.com
                Journal
                J Gastroenterol
                J Gastroenterol
                Journal of Gastroenterology
                Springer Singapore (Singapore )
                0944-1174
                1435-5922
                4 March 2021
                4 March 2021
                2021
                : 56
                : 4
                : 336-349
                Affiliations
                [1 ]GRID grid.412901.f, ISNI 0000 0004 1770 1022, Center of Infectious Diseases, , West China Hospital of Sichuan University, ; No. 37 Guoxue Alley, Wuhou District, Chengdu, 610041 Sichuan China
                [2 ]GRID grid.13291.38, ISNI 0000 0001 0807 1581, Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, , Sichuan University, ; No. 17 People’s South Road, Chengdu, 610041 Sichuan China
                [3 ]GRID grid.54549.39, ISNI 0000 0004 0369 4060, School of Medicine, , University of Electronic Science and Technology of China, ; No. 4 Section 2, North Jianshe Road, Chengdu, 610054 Sichuan China
                [4 ]GRID grid.410646.1, ISNI 0000 0004 1808 0950, Department of Hepatobiliary Surgery and Cell Transplantation Center, , Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, ; No. 32 Western Section 2, 1st Ring Rd., Chengdu, 610072 Sichuan China
                Article
                1765
                10.1007/s00535-021-01765-4
                8005397
                33665710
                65637c44-08bc-4e09-8c48-557bb1d49b98
                © The Author(s) 2021

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 19 November 2020
                : 23 January 2021
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100012226, Fundamental Research Funds for the Central Universities;
                Award ID: ZYGX2020KYQD002
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100013076, National Major Science and Technology Projects of China;
                Award ID: 2018ZX10715003
                Award Recipient :
                Funded by: 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University
                Award ID: ZYGD20009
                Award Recipient :
                Funded by: 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University
                Award ID: ZYJC18008
                Award Recipient :
                Categories
                Review
                Custom metadata
                © Japanese Society of Gastroenterology 2021

                Gastroenterology & Hepatology
                exosome,hepatitis virus,immune escape,immune response,exosomal nanoshuttle

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