ISGylation of Hepatitis C Virus NS5A Protein Promotes Viral RNA Replication via Recruitment of Cyclophilin A.
ISGylation
cyclophilin A
hepatitis C virus
interferon
viral replication
Journal
Journal of virology
ISSN: 1098-5514
Titre abrégé: J Virol
Pays: United States
ID NLM: 0113724
Informations de publication
Date de publication:
29 09 2020
29 09 2020
Historique:
received:
25
03
2020
accepted:
24
07
2020
pubmed:
31
7
2020
medline:
16
12
2020
entrez:
31
7
2020
Statut:
epublish
Résumé
Interferon-stimulated gene 15 (ISG15) is a ubiquitin-like protein that is covalently conjugated to many substrate proteins in order to modulate their functions; this conjugation is called ISGylation. Several groups reported that the ISGylation of hepatitis C virus (HCV) NS5A protein affects HCV replication. However, the ISG15 conjugation sites on NS5A are not well determined, and it is unclear whether the role of NS5A ISGylation in HCV replication is proviral or antiviral. Here, we investigated the role of NS5A ISGylation in HCV replication by using HCV RNA replicons that encode a mutation at each lysine (Lys) residue of the NS5A protein. Immunoblot analyses revealed that 5 Lys residues (K44, K68, K166, K215, and K308) of the 14 Lys residues within NS5A (genotype 1b, Con1) have the potential to accept ISGylation. We tested the NS5A ISGylation among different HCV genotypes and observed that the NS5A proteins of all of the HCV genotypes accept ISGylation at multiple Lys residues. Using an HCV luciferase reporter replicon assay revealed that residue K308 of NS5A is important for HCV (1b, Con1) RNA replication. We observed that K308, one of the Lys residues for NS5A ISGylation, is located within the binding region of cyclophilin A (CypA), which is the critical host factor for HCV replication. We obtained evidence derived from all of the HCV genotypes suggesting that NS5A ISGylation enhances the interaction between NS5A and CypA. Taken together, these results suggest that NS5A ISGylation functions as a proviral factor and promotes HCV replication via the recruitment of CypA.
Identifiants
pubmed: 32727878
pii: JVI.00532-20
doi: 10.1128/JVI.00532-20
pmc: PMC7527057
pii:
doi:
Substances chimiques
Cytokines
0
RNA, Viral
0
Ubiquitins
0
Viral Nonstructural Proteins
0
ISG15 protein, human
60267-61-0
NS-5 protein, hepatitis C virus
EC 2.7.7.48
Cyclophilin A
EC 5.2.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright © 2020 American Society for Microbiology.
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