2BC Non-Structural Protein of Enterovirus A71 Interacts with SNARE Proteins to Trigger Autolysosome Formation

Lai, J.K.F. and Sam, I.C. and Verlhac, P. and Baguet, J. and Eskelinen, E.L. and Faure, M. and Chan, Y.F. (2017) 2BC Non-Structural Protein of Enterovirus A71 Interacts with SNARE Proteins to Trigger Autolysosome Formation. Viruses, 9 (7). p. 169. ISSN 1999-4915, DOI https://doi.org/10.3390/v9070169.

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Official URL: http://dx.doi.org/10.3390/v9070169


Viruses have evolved unique strategies to evade or subvert autophagy machinery. Enterovirus A71 (EV-A71) induces autophagy during infection in vitro and in vivo. In this study, we report that EV-A71 triggers autolysosome formation during infection in human rhabdomyosarcoma (RD) cells to facilitate its replication. Blocking autophagosome-lysosome fusion with chloroquine inhibited virus RNA replication, resulting in lower viral titres, viral RNA copies and viral proteins. Overexpression of the non-structural protein 2BC of EV-A71 induced autolysosome formation. Yeast 2-hybrid and co-affinity purification assays showed that 2BC physically and specifically interacted with a N-ethylmaleimide-sensitive factor attachment receptor (SNARE) protein, syntaxin-17 (STX17). Co-immunoprecipitation assay further showed that 2BC binds to SNARE proteins, STX17 and synaptosome associated protein 29 (SNAP29). Transient knockdown of STX17, SNAP29, and microtubule-associated protein 1 light chain 3B (LC3B), crucial proteins in the fusion between autophagosomes and lysosomes) as well as the lysosomal-associated membrane protein 1 (LAMP1) impaired production of infectious EV-A71 in RD cells. Collectively, these results demonstrate that the generation of autolysosomes triggered by the 2BC non-structural protein is important for EV-A71 replication, revealing a potential molecular pathway targeted by the virus to exploit autophagy. This study opens the possibility for the development of novel antivirals that specifically target 2BC to inhibit formation of autolysosomes during EV-A71 infection.

Item Type: Article
Funders: Tamotsu Yoshimori (pmRFP-LC3; Osaka University, Osaka, Japan), Walther Mothes (LAMP1-YFP; Yale University School of Medicine, New Haven, USA), University of Malaya (High Impact Research Grant E000013-20001 and postgraduate research grant PG060-2015A), Ministry of Education, Malaysia (Fundamental Research Grant Scheme FP015-2012A and FP022-2014A), L’Oréal-UNESCO for Women in Science Malaysia Fellowship 2014 (PV001-2015), L’Oréal-UNESCO High Rising Talent Grant 2015 (IF006-2015), Institut Universitaire de France, ANR-14-CE14-0022, and Fondation pour la Recherche Médicale (FRM), Academy of Finland and the Magnus Ehrnrooth Foundation
Uncontrolled Keywords: Picornavirus; Enterovirus; Enterovirus A71; Replication; Autophagy; Autolysosome; Syntaxin-17; Synaptosome-associated protein of 29 kDa; SNARE; 2BC
Subjects: R Medicine
Divisions: Faculty of Medicine
Depositing User: Ms. Juhaida Abd Rahim
Date Deposited: 06 Sep 2018 01:10
Last Modified: 06 Sep 2018 01:10
URI: http://eprints.um.edu.my/id/eprint/19131

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