HCV NS5A and IRF9 compete for CypA binding

被引:24
作者
Bobardt, Michael
Hopkins, Sam [2 ]
Baugh, James
Chatterji, Udayan
Hernandez, Felicia
Hiscott, John [3 ]
Sluder, Ann [2 ]
Lin, Kai [4 ]
Gallay, Philippe A. [1 ]
机构
[1] Scripps Res Inst, IMM 9, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA
[2] SCYNEXIS Inc, Durham, NC 27713 USA
[3] Vaccine & Gene Therapy Inst Florida, Port St Lucie, FL 34987 USA
[4] Novartis Inst Biomed Res Inc, Cambridge, MA 02139 USA
关键词
HCV; NS5A; cyclophilin A; cyclophilin inhibitors; IFN; HEPATITIS-C VIRUS; NONSTRUCTURAL 5A PROTEIN; REPLICATION IN-VITRO; HUMAN CYCLOPHILIN-A; RNA REPLICATION; CYCLOSPORINE-A; ACTIVE-SITE; ALPHA/BETA INTERFERON; ISOMERASE ACTIVITY; GENE-EXPRESSION;
D O I
10.1016/j.jhep.2012.08.007
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
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. (C) 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
引用
收藏
页码:16 / 23
页数:8
相关论文
共 51 条
[1]   Induction of type I interferon by RNA viruses: cellular receptors and their substrates [J].
Baum, Alina ;
Garcia-Sastre, Adolfo .
AMINO ACIDS, 2010, 38 (05) :1283-1299
[2]   Intrahepatic gene expression during chronic hepatitis C virus infection in chimpanzees [J].
Bigger, CB ;
Guerra, B ;
Brasky, KM ;
Hubbard, G ;
Beard, MR ;
Luxon, BA ;
Lemon, SM ;
Lanford, RE .
JOURNAL OF VIROLOGY, 2004, 78 (24) :13779-13792
[3]   DNA microarray analysis of chimpanzee liver during acute resolving hepatitis C virus infection [J].
Bigger, CB ;
Brasky, KM ;
Lanford, RE .
JOURNAL OF VIROLOGY, 2001, 75 (15) :7059-7066
[4]  
Biron CA, 1999, CURR OPIN MICROBIOL, V2, P374
[5]   Interferons: Signaling, antiviral and viral evasion [J].
Bonjardim, Claudio A. ;
Ferreira, Paulo C. P. ;
Kroon, Erna G. .
IMMUNOLOGY LETTERS, 2009, 122 (01) :1-11
[6]   HCV resistance to cyclosporin A does not correlate with a resistance of the NS5A-cyclophilin A interaction to cyclophilin inhibitors [J].
Chatterji, Udayan ;
Lim, Precious ;
Bobardt, Michael D. ;
Wieland, Stefan ;
Cordek, Daniel G. ;
Vuagniaux, Gregoire ;
Chisari, Francis ;
Cameron, Craig E. ;
Targett-Adams, Paul ;
Parkinson, Tanya ;
Gallay, Philippe A. .
JOURNAL OF HEPATOLOGY, 2010, 53 (01) :50-56
[7]   The Isomerase Active Site of Cyclophilin A Is Critical for Hepatitis C Virus Replication [J].
Chatterji, Udayan ;
Bobardt, Michael ;
Selvarajah, Suganya ;
Yang, Feng ;
Tang, Hengli ;
Sakamoto, Noayo ;
Vuagniaux, Gregoire ;
Parkinson, Tanya ;
Gallay, Philippe .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2009, 284 (25) :16998-17005
[8]   DEB025 (Alisporivir) Inhibits Hepatitis C Virus Replication by Preventing a Cyclophilin A Induced Cis-Trans Isomerisation in Domain II of NS5A [J].
Coelmont, Lotte ;
Hanoulle, Xavier ;
Chatterji, Udayan ;
Berger, Carola ;
Snoeck, Joke ;
Bobardt, Michael ;
Lim, Precious ;
Vliegen, Inge ;
Paeshuyse, Jan ;
Vuagniaux, Gregoire ;
Vandamme, Anne-Mieke ;
Bartenschlager, Ralf ;
Gallay, Philippe ;
Lippens, Guy ;
Neyts, Johan .
PLOS ONE, 2010, 5 (10)
[9]   Sensitivity of hepatitis C virus to cyclosporine a depends on nonstructural proteins NS5A and NS5B [J].
Fernandes, Fiona ;
Poole, Daniel S. ;
Hoover, Spencer ;
Middleton, Rannveig ;
Andrei, Adin-Cristian ;
Gerstner, Justin ;
Striker, Rob .
HEPATOLOGY, 2007, 46 (04) :1026-1033
[10]   Cyclosporine Inhibits a Direct Interaction between Cyclophilins and Hepatitis C NS5A [J].
Fernandes, Fiona ;
Ansari, Israr-ul H. ;
Striker, Rob .
PLOS ONE, 2010, 5 (03)