tetano
Editor, Senior Moderator
J Virol. 2014 May 28. pii: JVI.00424-14. [Epub ahead of print]
Activation of c-jun N-terminal kinase upon Influenza AVirus (IAV) infection is independent of pathogen related receptors, but dependent on amino acid sequence variations of the IAV NS1.
Nacken W1, Anhlan D1, Hrincius ER1, Mostafa A2, Wolff T3, Sadewasser A3, Pleschka S4, Ehrhardt C5, Ludwig S6.
Author information
Abstract
A hallmark cell response to influenza A virus (IAV) infections is the phosphorylation and activation of c-jun N-terminal kinase (JNK). However, so far it is not fully clear which molecules are involved in the activation of JNK upon IAV infection. Here, we report that the transfection of influenza viral RNA induces JNK in a RIG-I dependent manner. However, neither RIG-I like receptors nor MyD88 dependent toll like receptors were found to be involved in the activation of JNK upon IAV infection. Viral JNK activation could be blocked by addition of cycloheximide and heat shock protein inhibitors during infection suggesting that the expression of an IAV encoded protein is responsible for JNK activation. Indeed, the over expression of the non-structural protein NS1 of certain IAV subtypes activated JNK, whereas those of some other subtypes failed to activate JNK. Site directed mutagenesis experiments using NS1 of IAV H7N7, H5N1 and H3N2 subtypes identified the amino acid (aa) residue phenylalanine (F) at position 103 to be decisive for JNK activation. The cleavage and polyadenylation specific factor 30 (CPSF30), whose binding to NS1 is stabilised by the aa F103 and M106, is not involved in JNK activation. Conclusively, subtype specific sequence variations in the IAV NS1 protein result in subtype specific differences in JNK signaling upon IAV infection.
IMPORTANCE:
Influenza A virus (IAV) infection leads to the activation or modulation of multiple signalling pathways. Here, we demonstrate for the first time, that the c-jun N-terminal kinase (JNK), a long known stress activated MAP kinase, is activated by Rig-I when cells are treated with IAV RNA. However, on the same time, the non-structural protein 1 (NS1) of IAV has an intrinsic JNK activating property that is dependent on IAV subtype specific amino acid variations around position 103. Our findings identify two different and independent pathways that result in the activation of JNK in course of an IAV infection.
Copyright ? 2014, American Society for Microbiology. All Rights Reserved.
PMID:
24872593
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/24872593
Activation of c-jun N-terminal kinase upon Influenza AVirus (IAV) infection is independent of pathogen related receptors, but dependent on amino acid sequence variations of the IAV NS1.
Nacken W1, Anhlan D1, Hrincius ER1, Mostafa A2, Wolff T3, Sadewasser A3, Pleschka S4, Ehrhardt C5, Ludwig S6.
Author information
Abstract
A hallmark cell response to influenza A virus (IAV) infections is the phosphorylation and activation of c-jun N-terminal kinase (JNK). However, so far it is not fully clear which molecules are involved in the activation of JNK upon IAV infection. Here, we report that the transfection of influenza viral RNA induces JNK in a RIG-I dependent manner. However, neither RIG-I like receptors nor MyD88 dependent toll like receptors were found to be involved in the activation of JNK upon IAV infection. Viral JNK activation could be blocked by addition of cycloheximide and heat shock protein inhibitors during infection suggesting that the expression of an IAV encoded protein is responsible for JNK activation. Indeed, the over expression of the non-structural protein NS1 of certain IAV subtypes activated JNK, whereas those of some other subtypes failed to activate JNK. Site directed mutagenesis experiments using NS1 of IAV H7N7, H5N1 and H3N2 subtypes identified the amino acid (aa) residue phenylalanine (F) at position 103 to be decisive for JNK activation. The cleavage and polyadenylation specific factor 30 (CPSF30), whose binding to NS1 is stabilised by the aa F103 and M106, is not involved in JNK activation. Conclusively, subtype specific sequence variations in the IAV NS1 protein result in subtype specific differences in JNK signaling upon IAV infection.
IMPORTANCE:
Influenza A virus (IAV) infection leads to the activation or modulation of multiple signalling pathways. Here, we demonstrate for the first time, that the c-jun N-terminal kinase (JNK), a long known stress activated MAP kinase, is activated by Rig-I when cells are treated with IAV RNA. However, on the same time, the non-structural protein 1 (NS1) of IAV has an intrinsic JNK activating property that is dependent on IAV subtype specific amino acid variations around position 103. Our findings identify two different and independent pathways that result in the activation of JNK in course of an IAV infection.
Copyright ? 2014, American Society for Microbiology. All Rights Reserved.
PMID:
24872593
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/24872593