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Inhibition of Arenavirus Entry and Replication by the Cell-Intrinsic Restriction Factor ZMPSTE24 Is Enhanced by IFITM Antiviral Activity

Stott-Marshall, Robert J.; Foster, Toshana L.

Inhibition of Arenavirus Entry and Replication by the Cell-Intrinsic Restriction Factor ZMPSTE24 Is Enhanced by IFITM Antiviral Activity Thumbnail


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Abstract

In the absence of effective vaccines and treatments, annual outbreaks of severe human haemorrhagic fever caused by arenaviruses, such as Lassa virus, continue to pose a significant human health threat. Understanding the balance of cellular factors that inhibit or promote arenavirus infection may have important implications for the development of effective antiviral strategies. Here, we identified the cell-intrinsic zinc transmembrane metalloprotease, ZMPSTE24, as a restriction factor against arenaviruses. Notably, CRISPR-Cas9-mediated knockout of ZMPSTE24 in human alveolar epithelial A549 cells increased arenavirus glycoprotein-mediated viral entry in pseudoparticle assays and live virus infection models. As a barrier to viral entry and replication, ZMPSTE24 may act as a downstream effector of interferon-induced transmembrane protein (IFITM) antiviral function; though through a yet poorly understood mechanism. Overexpression of IFITM1, IFITM2, and IFITM3 proteins did not restrict the entry of pseudoparticles carrying arenavirus envelope glycoproteins and live virus infection. Furthermore, gain-of-function studies revealed that IFITMs augment the antiviral activity of ZMPSTE24 against arenaviruses, suggesting a cooperative effect of viral restriction. We show that ZMPSTE24 and IFITMs affect the kinetics of cellular endocytosis, suggesting that perturbation of membrane structure and stability is likely the mechanism of ZMPSTE24-mediated restriction and cooperative ZMPSTE24-IFITM antiviral activity. Collectively, our findings define the role of ZMPSTE24 host restriction activity in the early stages of arenavirus infection. Moreover, we provide insight into the importance of cellular membrane integrity for productive fusion of arenaviruses and highlight a novel avenue for therapeutic development.

Journal Article Type Article
Acceptance Date Jan 31, 2022
Online Publication Date Feb 18, 2022
Publication Date Feb 18, 2022
Deposit Date Feb 21, 2022
Publicly Available Date Feb 21, 2022
Journal Frontiers in Microbiology
Electronic ISSN 1664-302X
Peer Reviewed Peer Reviewed
Volume 13
Article Number 840885
DOI https://doi.org/10.3389/fmicb.2022.840885
Keywords arenavirus; Lassa virus; ZMPSTE24; interferon-induced transmembrane 11 proteins (IFITMs); cell-intrinsic factors, innate immunity 12 13
Public URL https://nottingham-repository.worktribe.com/output/7500953
Publisher URL https://www.frontiersin.org/articles/10.3389/fmicb.2022.840885/full

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