Hepatitis C virus NS5A targets the nucleosome assembly protein NAP1L1 to control the innate cellular response

Çevik, R. E., Cesarec, M., Da Silva Filipe, A., Licastro, D., McLauchlan, J. and Marcello, A. (2017) Hepatitis C virus NS5A targets the nucleosome assembly protein NAP1L1 to control the innate cellular response. Journal of Virology, 91(18), e00880-17. (doi:10.1128/JVI.00880-17) (PMID:28659470)

[img]
Preview
Text
143947.pdf - Accepted Version

4MB

Abstract

Hepatitis C virus (HCV) is a single-stranded positive-sense RNA hepatotropic virus. Despite cellular defenses, HCV is able to replicate in hepatocytes and to establish a chronic infection that could lead to severe complications and hepatocellular carcinoma. An important player in subverting the host response to HCV infection is the viral non-structural protein NS5A that, in addition to its role in replication and assembly, targets several pathways involved in the cellular response to viral infection. Several unbiased screens identified the nucleosome-assembly protein 1-like 1 (NAP1L1) as an interaction partner of HCV NS5A. Here we confirm this interaction and map it to the C-terminus of NS5A of both genotype 1 and 2. NS5A sequesters NAP1L1 in the cytoplasm blocking its nuclear translocation. However, only NS5A from genotype 2 HCV, but not from genotype 1, targets NAP1L1 for proteosomal-mediated degradation. NAP1L1 is a nuclear chaperone involved in chromatin remodeling and we demonstrate the NAP1L1-dependent regulation of specific pathways involved in cellular responses to viral infection and cell survival. Among those we show that lack of NAP1L1 leads to a decrease of RELA protein levels and a strong defect of IRF3 TBK1/IKKϵ-mediated phosphorylation leading to inefficient RIG-I and TLR3 responses. Hence, HCV is able to modulate the host cell environment by targeting NAP1L1 through NS5A.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Da Silva Filipe, Dr Ana and McLauchlan, Professor John
Authors: Çevik, R. E., Cesarec, M., Da Silva Filipe, A., Licastro, D., McLauchlan, J., and Marcello, A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Journal of Virology
Publisher:American Society for Microbiology
ISSN:0022-538X
ISSN (Online):1098-5514
Published Online:28 June 2017
Copyright Holders:Copyright © 2017 American Society for Microbiology
First Published:First published in Journal of Virology 91(18):e00880-17
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

University Staff: Request a correction | Enlighten Editors: Update this record