The two-stage interaction of Ebola virus VP40 with nucleoprotein results in a switch from viral RNA synthesis to virion
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Protein & Cell
RESEARCH ARTICLE The two-stage interaction of Ebola virus VP40 with nucleoprotein results in a switch from viral RNA synthesis to virion assembly/ budding 1
State Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan 430072, China 2 Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China & Correspondence: [email protected] (Y. Qin), [email protected] (M. Chen) Received April 12, 2020 Accepted July 6, 2020
ABSTRACT Ebola virus (EBOV) is an enveloped negative-sense RNA virus and a member of the filovirus family. Nucleoprotein (NP) expression alone leads to the formation of inclusion bodies (IBs), which are critical for viral RNA synthesis. The matrix protein, VP40, not only plays a critical role in virus assembly/budding, but also can regulate transcription and replication of the viral genome. However, the molecular mechanism by which VP40 regulates viral RNA synthesis and virion assembly/budding is unknown. Here, we show that within IBs the N-terminus of NP recruits VP40 and is required for VLP-containing NP release. Furthermore, we find four point mutations (L692A, P697A, P698A and W699A) within the C-terminal hydrophobic core of NP result in a stronger VP40–NP interaction within IBs, sequestering VP40 within IBs, reducing VP40–VLP egress, abolishing the incorporation of NC-like structures into VP40–VLP, and inhibiting viral RNA synthesis, suggesting that the interaction of N-terminus of NP with VP40 induces a conformational change in the C-terminus of NP. Consequently, the C-terminal hydrophobic core of NP is exposed and binds VP40, thereby inhibiting RNA synthesis and initiating virion assembly/budding.
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13238-020-00764-0) contains supplementary material, which is available to authorized users.
© The Author(s) 2020
KEYWORDS Ebola virus, nucleoprotein, matrix protein, two-stage interaction, RNA synthesis, nucleocapsid, assembly/budding
INTRODUCTION The Ebola virus (EBOV) is an enveloped non-segmented negative strand RNA virus (NNSV) and a member of the filovirus family, which consists of three genera, Ebolavirus, Marburgvirus, and Cuevavirus. The species Zaire, Sudan, Bundibugyo, Tai Forest, and Reston ebolavirus are found within the genus of Ebolavirus. Marburgvirus and Cuevavirus each include one species: Marburg virus (MARV) and Lloviu virus (LLOV), respectively (Negredo et al., 2011; Misasi and Sullivan, 2014; Martin et al., 2016; Yang et al., 2019). EBOV can cause a severe fever with a high fatality rate. The outbreak of EBOV in the Democratic Republic Congo from August 2018 to November 2019 caused 3,296 infections and 2,196 deaths (67%), making it the second largest outbreak since the 2014–2016 outbreak in West Africa (Hartman et al., 2010; Messaoudi et al., 2015; Vetter et al., 2016; Aruna et al., 2019; Hoenen et al., 2019). The EBOV genome is approximately 19 kb in length, encoding seven structural proteins: nucleopr
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