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Cathepsin W is required for escape of influenza a virus from late endosomes


Edinger, T O; Pohl, M O; Yangüez, E; Stertz, S (2015). Cathepsin W is required for escape of influenza a virus from late endosomes. mBio, 6(3):e00297-15.

Abstract

Human cathepsinW(CtsW) is a cysteine protease, which was identified in a genome-wide RNA interference (RNAi)
screen to be required for influenza A virus (IAV) replication. In this study, we show that reducing the levels of expression of CtsW reduces viral titers for different subtypes of IAV, and we map the target step of CtsW requirement to viral entry. Using a set of small interfering RNAs (siRNAs) targeting CtsW, we demonstrate that knockdown of CtsW results in a decrease of IAV
nucleoprotein accumulation in the nuclei of infected cells at 3 h postinfection. Assays specific for the individual stages of IAV entry further show that attachment, internalization, and early endosomal trafficking are not affected by CtsW knockdown. However, we detected impaired escape of viral particles from late endosomes in CtsW knockdown cells. Moreover, fusion analysis with a dual-labeled influenza virus revealed a significant reduction in fusion events, with no detectable impact on endosomal pH, suggesting that CtsW is required at the stage of viral fusion. The defect in IAV entry upon CtsW knockdown could be rescued by ectopic expression of wild-type CtsW but not by the expression of a catalytically inactive mutant of CtsW, suggesting that the proteolytic activity of CtsW is required for successful entry of IAV. Our results establish CtsW as an important host factor for
entry of IAV into target cells and suggest that CtsW could be a promising target for the development of future antiviral drugs.

Abstract

Human cathepsinW(CtsW) is a cysteine protease, which was identified in a genome-wide RNA interference (RNAi)
screen to be required for influenza A virus (IAV) replication. In this study, we show that reducing the levels of expression of CtsW reduces viral titers for different subtypes of IAV, and we map the target step of CtsW requirement to viral entry. Using a set of small interfering RNAs (siRNAs) targeting CtsW, we demonstrate that knockdown of CtsW results in a decrease of IAV
nucleoprotein accumulation in the nuclei of infected cells at 3 h postinfection. Assays specific for the individual stages of IAV entry further show that attachment, internalization, and early endosomal trafficking are not affected by CtsW knockdown. However, we detected impaired escape of viral particles from late endosomes in CtsW knockdown cells. Moreover, fusion analysis with a dual-labeled influenza virus revealed a significant reduction in fusion events, with no detectable impact on endosomal pH, suggesting that CtsW is required at the stage of viral fusion. The defect in IAV entry upon CtsW knockdown could be rescued by ectopic expression of wild-type CtsW but not by the expression of a catalytically inactive mutant of CtsW, suggesting that the proteolytic activity of CtsW is required for successful entry of IAV. Our results establish CtsW as an important host factor for
entry of IAV into target cells and suggest that CtsW could be a promising target for the development of future antiviral drugs.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Virology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:9 June 2015
Deposited On:15 Feb 2016 15:28
Last Modified:03 Aug 2017 17:23
Publisher:American Society for Microbiology
ISSN:2150-7511
Funders:Swiss National Science Foundation (31003A_135278), Doctoral grant from the AXA Research Fund
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1128/mBio.00297-15
PubMed ID:26060270

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