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J Hepatol. 2013 Jan;58(1):16-23. doi: 10.1016/j.jhep.2012.08.007. Epub 2012 Aug 15.

HCV NS5A and IRF9 compete for CypA binding.

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  • 1Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.

Abstract

BACKGROUND & AIMS:

Cyclophilin A (CypA) is vital for HCV replication. Cyp inhibitors successfully decrease viral loads in HCV-infected patients. However, their mechanisms of action remain unknown. Since interferon (IFN) can also suppress HCV replication, we asked whether a link between CypA and the IFN response exists.

METHODS:

We used cellular and recombinant pulldown approaches to investigate the possibility of a specific association of CypA with host ligands.

RESULTS:

We found for the first time that CypA binds to a major component of the IFN response - the IFN regulatory factor 9 (IRF9). IRF9 is the DNA-binding component of the transcriptional IFN-stimulated gene factor 3 (ISGF3). CypA binds directly to IRF9 via its peptidyl-prolyl isomerase (PPIase) pocket. Cyp inhibitors such as cyclosporine A (CsA) or non-immunosuppressive derivates such as alisporivir and SCY-635, prevent IRF9-CypA complex formation. CypA binds to the C-terminal IRF-association-domain (IAD), but not to the DNA-binding or linker domains of IRF9. Remarkably, CypA associates with the multimeric ISGF3 complex. We also obtained evidence that CypA neutralization enhances IFN-induced transcription. Interestingly, the hepatitis C virus (HCV) non-structural 5A (NS5A) protein, which is known to modulate the IFN response, competes with IRF9 for CypA binding and can prevent the formation of IRF9-CypA complexes.

CONCLUSIONS:

This study demonstrates for the first time that CypA binds specifically to a component of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, IRF9. This study also reveals a novel opportunity of HCV to modulate the IFN response via NS5A.

Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

PMID:
22902549
[PubMed - indexed for MEDLINE]
PMCID:
PMC3527675
Free PMC Article
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