title: 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.affiliation: Department of Microbiology and Immunology, Gate 11, Royal Parade, The University of Melbourne, Melbourne, Victoria 3010, Australia. hollg@unimelb.edu.au
authors.forename: Gavan
authors.initials: G
authors.lastname: Holloway
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Coulson
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D002460:Cell Line; D016758:Genes, jun; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000821:virology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008253:Macaca mulatta; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012401:Rotavirus / Q000472:pathogenicity* / Q000502:physiology*; D012400:Rotavirus Infections / Q000235:genetics / Q000378:metabolism / Q000821:virology; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic; D015678:Viral Structural Proteins / Q000235:genetics; D014779:Virus Replication; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D016209:Interleukin-8; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D015678:Viral Structural Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases