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)

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 > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
• 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