CRK adaptor protein expression is required for efficient replication of avian influenza A viruses and controls JNK-mediated apoptotic responses
Article first published online: 20 JAN 2010
© 2010 Blackwell Publishing Ltd
Volume 12, Issue 6, pages 831–843, June 2010
How to Cite
Hrincius, E. R., Wixler, V., Wolff, T., Wagner, R., Ludwig, S. and Ehrhardt, C. (2010), CRK adaptor protein expression is required for efficient replication of avian influenza A viruses and controls JNK-mediated apoptotic responses. Cellular Microbiology, 12: 831–843. doi: 10.1111/j.1462-5822.2010.01436.x
- Issue published online: 5 MAY 2010
- Article first published online: 20 JAN 2010
- Received 3 September, 2009; revised 7 December, 2009; accepted 27 December, 2009.
The non-structural protein 1 (A/NS1) of influenza A viruses (IAV) harbours several src-homology domain (SH) binding motifs that are required for interaction with cellular proteins. The SH3 binding motif at aa212-217 [PPLPPK] of A/NS1 was shown to be essential for binding to the cellular adaptor proteins CRK and CRKL. Both regulate diverse cellular effector pathways, including activation of the MAP-kinase JNK that in turn mediates antiviral responses to IAV infection. By studying functional consequences of A/NS1–CRK interaction we show here that A/NS1 binding to CRK contributes to suppression of the antiviral-acting JNK–ATF2 pathway. However, only IAV that encode an A/NS1-protein harbouring the CRK/CRKL SH3 binding motif PPLPPK were attenuated upon downregulation of CRKI/II and CRKL, but not of CRKII alone. The PPLPPK site-harbouring candidate strains could be discriminated from other strains by a pronounced viral activation of the JNK–ATF2 signalling module that was even further boosted upon knock-down of CRKI/II. Interestingly, this enhanced JNK activation did not alter type-I IFN-expression, but rather resulted in increased levels of virus-induced cell death. Our results imply that binding capacity of A/NS1 to CRK/CRKL has evolved in virus strains that over-induce the antiviral acting JNK–ATF2 signalling module and helps to suppress the detrimental apoptosis promoting action of this pathway.