Rotavirus activates JNK and p38 signaling pathways in intestinal cells, leading to AP-1-driven transcriptional responses and enhanced virus replication.

Abstract

Rotavirus infection is known to regulate transcriptional changes in many cellular genes. The transcription factors NF-kappaB 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.

• Authors: Gavan Holloway, Barbara S Coulson
• Journal: Journal of virology (J Virol) Vol. 80 Issue 21 Pg. 10624-33 (Nov 2006) ISSN: 0022-538X [Print] United States
• PMID: 16928761 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-8
• RNA, Messenger
• Transcription Factor AP-1
• Viral Structural Proteins
• JNK Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases

Topics

• Animals
• Caco-2 Cells
• Cell Line
• Genes, jun
• Humans
• Interleukin-8 (genetics)
• Intestinal Mucosa (metabolism)
• Intestines (virology)
• JNK Mitogen-Activated Protein Kinases (metabolism)
• MAP Kinase Signaling System
• Macaca mulatta
• RNA, Messenger (biosynthesis, genetics)
• Rotavirus (pathogenicity, physiology)
• Rotavirus Infections (genetics, metabolism, virology)
• Transcription Factor AP-1 (metabolism)
• Transcription, Genetic
• Viral Structural Proteins (genetics)
• Virus Replication
• p38 Mitogen-Activated Protein Kinases (metabolism)