HCV NS5A and IRF9 compete for CypA binding.
HCV NS5A and IRF9 compete for CypA binding.
复制标题
HCV NS5A 和 IRF9 竞争 CypA 结合。
DOI：
10.1016/j.jhep.2012.08.007
复制
发表时间：
2013-01
影响因子：
25.7
通讯作者：
Gallay, Philippe A.
中科院分区：
文献类型：
--
作者：
Bobardt, Michael;Hopkins, Sam;Baugh, James;Chatterji, Udayan;Hernandez, Felicia;Hiscott, John;Sluder, Ann;Lin, Kai;Gallay, Philippe A.
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. We used cellular and recombinant pulldown approaches to investigate the possibility of a specific association of CypA with host ligands. 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 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) nonstructural 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. 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.
登录
查看更多内容
影响因子：
5.9
作者：
Levy, David E.;Marie, Isabelle J.;Durbin, Joan E.
通讯作者：
Durbin, Joan E.
影响因子：
3.5
作者：
Baum, Alina;Garcia-Sastre, Adolfo
通讯作者：
Garcia-Sastre, Adolfo
影响因子：
3.7
作者：
Coelmont L;Hanoulle X;Chatterji U;Berger C;Snoeck J;Bobardt M;Lim P;Vliegen I;Paeshuyse J;Vuagniaux G;Vandamme AM;Bartenschlager R;Gallay P;Lippens G;Neyts J
通讯作者：
Neyts J
影响因子：
5.4
作者：
Bigger, CB;Guerra, B;Lanford, RE
通讯作者：
Lanford, RE
影响因子：
2.9
作者：
Hennig, L;Christner, C;Fischer, G
通讯作者：
Fischer, G