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Journal of Virology, November 2006, p. 10624-10633, Vol. 80, No. 21
0022-538X/06/$08.00+0     doi:10.1128/JVI.00390-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Rotavirus Activates JNK and p38 Signaling Pathways in Intestinal Cells, Leading to AP-1-Driven Transcriptional Responses and Enhanced Virus Replication{triangledown}

Gavan Holloway* and Barbara S. Coulson

Department of Microbiology and Immunology, The University of Melbourne, Melbourne, Victoria 3010, Australia

Received 23 February 2006/ Accepted 14 August 2006

Rotavirus infection is known to regulate transcriptional changes in many cellular genes. The transcription factors NF-{kappa}B and AP-1 are activated by rotavirus infection, but the upstream processes leading to these events are largely unidentified. We therefore studied the activation state during rotavirus infection of c-Jun NH2-terminal kinase (JNK) and p38, which are kinases known to activate AP-1. As assessed by Western blotting using phospho-specific antibodies, infection with rhesus rotavirus (RRV) or exposure to UV-psoralen-inactivated RRV (I-RRV) resulted in the activation of JNK in HT-29, Caco-2, and MA104 cells. Activation of p38 during RRV infection was observed in Caco-2 and MA104 cells but not in HT-29 cells, whereas exposure to I-RRV did not lead to p38 activation in these cell lines. Rotavirus strains SA11, CRW-8, Wa, and UK also activated JNK and p38. Consistent with the activation of JNK, a corresponding increase in the phosphorylation of the AP-1 component c-Jun was shown. The interleukin-8 (IL-8) and c-jun promoters contain AP-1 binding sequences, and these genes have been shown previously to be transcriptionally up-regulated during rotavirus infection. Using specific inhibitors of JNK (SP600125) and p38 (SB203580) and real-time PCR, we showed that maximal RRV-induced IL-8 and c-jun transcription required JNK and p38 activity. This highlights the importance of JNK and p38 in RRV-induced, AP-1-driven gene expression. Significantly, inhibition of p38 or JNK in Caco-2 cells reduced RRV growth but not viral structural antigen expression, demonstrating the potential importance of JNK and p38 activation for optimal rotavirus replication.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Gate 11, Royal Parade, The University of Melbourne, Melbourne, Victoria 3010, Australia. Phone: 61 3 8344 5715. Fax: 61 3 9347 1540. E-mail: hollg{at}unimelb.edu.au.

{triangledown} Published ahead of print on 23 August 2006.

Journal of Virology, November 2006, p. 10624-10633, Vol. 80, No. 21
0022-538X/06/$08.00+0     doi:10.1128/JVI.00390-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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