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      Endophilin-A2-mediated endocytic pathway is critical for enterovirus 71 entry into caco-2 cells

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          ABSTRACT

          Enterovirus 71 (EV71) is typically transmitted by the oral-faecal route and initiates infection upon crossing the intestinal mucosa. Our limited understanding of the mechanisms by which it crosses the intestinal mucosa has hampered the development of effective therapeutic options. Here, using an RNA interference screen combined with chemical inhibitors or the overexpression of dominant negative proteins, we found that EV71 entry into Caco-2 cells, a polarized human intestinal epithelial cell line, does not involve clathrin- and caveolae-dependent endocytic pathways or macropinocytosis but requires GTP-binding protein dynamin 2 and cytoskeleton remodelling. The use of siRNAs targeting endophilin family members revealed that endophlin-A2 is essential for the uptake of EV71 particles by Caco-2 cells. Subcellular analysis revealed that internalized EV71 virions largely colocalized with endophilin-A2 at cytomembrane ruffles and in the perinuclear area. Combined with viral entry kinetics, these data suggest that EV71 enters Caco-2 cells mainly via an endophilin-A2-mediated endocytic (EME) pathway. Finally, we showed that internalized EV71 virions were transported to endosomal sorting complex required for transport (ESCRT)-related multivesicular bodies (MVBs). These data provide attractive therapeutic targets to block EV71 infection.

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          Most cited references36

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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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            Protein modules and signalling networks.

            T. Pawson (1995)
            Communication between cells assumes particular importance in multicellular organisms. The growth, migration and differentiation of cells in the embryo, and their organization into specific tissues, depend on signals transmitted from one cell to another. In the adult, cell signalling orchestrates normal cellular behaviour and responses to wounding and infection. The consequences of breakdowns in this signalling underlie cancer, diabetes and disorders of the immune and cardiovascular systems. Conserved protein domains that act as key regulatory participants in many of these different signalling pathways are highlighted.
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              Virus-induced Abl and Fyn kinase signals permit coxsackievirus entry through epithelial tight junctions.

              Group B coxsackieviruses (CVBs) must cross the epithelium as they initiate infection, but the mechanism by which this occurs remains uncertain. The coxsackievirus and adenovirus receptor (CAR) is a component of the tight junction and is inaccessible to virus approaching from the apical surface. Many CVBs also interact with the GPI-anchored protein decay-accelerating factor (DAF). Here, we report that virus attachment to DAF on the apical cell surface activates Abl kinase, triggering Rac-dependent actin rearrangements that permit virus movement to the tight junction. Within the junction, interaction with CAR promotes conformational changes in the virus capsid that are essential for virus entry and release of viral RNA. Interaction with DAF also activates Fyn kinase, an event that is required for the phosphorylation of caveolin and transport of virus into the cell within caveolar vesicles. CVBs thus exploit DAF-mediated signaling pathways to surmount the epithelial barrier.
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                Author and article information

                Journal
                Emerg Microbes Infect
                Emerg Microbes Infect
                TEMI
                temi20
                Emerging Microbes & Infections
                Taylor & Francis
                2222-1751
                2019
                28 May 2019
                : 8
                : 1
                : 773-786
                Affiliations
                [a ]Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University Shanghai, People’s Republic of China
                [b ]General Hospital of the Tibet Military Area Command , Tibet, People’s Republic of China
                [c ]Company 7, Department of Clinical Medicine, Second Military Medical University Shanghai, People’s Republic of China
                Author notes
                [CONTACT ] Yong-Zhe Zhu zhuyongzhe1984@ 123456sina.com Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University , No. 800, Xiangyin Road, Shanghai200433, China
                Zhong-Tian Qi qizt@ 123456smmu.edu.cn Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University , No. 800, Xiangyin Road, Shanghai200433, China
                [*]

                These authors contribute equally to this work.

                Article
                1618686
                10.1080/22221751.2019.1618686
                6542187
                31132962
                2490462d-6260-4a8c-8278-9584ee3c83fe
                © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group, on behalf of Shanghai Shangyixun Cultural Communication Co., Ltd

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 20 December 2018
                : 08 May 2019
                : 09 May 2019
                Page count
                Figures: 6, Tables: 0, Equations: 0, References: 43, Pages: 14
                Funding
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Award ID: 31770181
                Award ID: 31770187
                Award ID: 81521091
                Funded by: Creativity and Innovation Training Program of Navy Military Medical University
                Award ID: FH2018048
                Funded by: National S&T Major Project for Infectious Diseases Control
                Award ID: 2017ZX10304403003-006
                Award ID: 2017ZX10304403003-007
                This work was funded by the National Natural Science Foundation of China (31770181, 31770187 and 81521091), and the National S&T Major Project for Infectious Diseases Control (2017ZX10304403003-006 and 2017ZX10304403003-007), and the Creativity and Innovation Training Program of Navy Military Medical University (FH2018048).
                Categories
                Article

                enterovirus 71,viral entry,endophilin,intestinal epithelial cells,endocytosis

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