Mutation of CD2AP and SH3KBP1 binding motif in alphavirus nsP3 hypervariable domain results in attenuated virus

Mutso, M. et al. (2018) Mutation of CD2AP and SH3KBP1 binding motif in alphavirus nsP3 hypervariable domain results in attenuated virus. Viruses, 10(5), 226. (doi:10.3390/v10050226) (PMID:29702546)

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Infection by Chikungunya virus (CHIKV) of the Old World alphaviruses (family Togaviridae) in humans can cause arthritis and arthralgia. The virus encodes four non-structural proteins (nsP) (nsP1, nsp2, nsP3 and nsP4) that act as subunits of the virus replicase. These proteins also interact with numerous host proteins and some crucial interactions are mediated by the unstructured C-terminal hypervariable domain (HVD) of nsP3. In this study, a human cell line expressing EGFP tagged with CHIKV nsP3 HVD was established. Using quantitative proteomics, it was found that CHIKV nsP3 HVD can bind cytoskeletal proteins, including CD2AP, SH3KBP1, CAPZA1, CAPZA2 and CAPZB. The interaction with CD2AP was found to be most evident; its binding site was mapped to the second SH3 ligand-like element in nsP3 HVD. Further assessment indicated that CD2AP can bind to nsP3 HVDs of many different New and Old World alphaviruses. Mutation of the short binding element hampered the ability of the virus to establish infection. The mutation also abolished ability of CD2AP to co-localise with nsP3 and replication complexes of CHIKV; the same was observed for Semliki Forest virus (SFV) harbouring a similar mutation. Similar to CD2AP, its homolog SH3KBP1 also bound the identified motif in CHIKV and SFV nsP3.

Item Type:Articles
Additional Information:The project was funded by European Regional Development Fund through the Centre of Excellence in Molecular Cell Engineering, Estonia, 2014-2020.4.01.15-013 and institutional research funding (IUT20-27) from Estonian Research Council to AM and Swedish Research Council (621-2014-4718) and Swedish Cancer Society (CAN 2015/751) to GMM.
Keywords:CD2AP, Chikungunya virus, SH3 ligand, SH3KBP1, alphavirus, proteomics.
Glasgow Author(s) Enlighten ID:Varjak, Dr Margus
Authors: Mutso, M., Morro, A. M., Smedberg, C., Kasvandik, S., Aquilimeba, M., Teppor, M., Tarve, L., Lulla, A., Lulla, V., Saul, S., Thaa, B., McInerney, G. M., Merits, A., and Varjak, M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Viruses
ISSN (Online):1999-4915
Published Online:27 April 2018
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Viruses 10(5): 226
Publisher Policy:Reproduced under a Creative Commons License

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