miR-132 regulates antiviral innate immunity through suppression of the p300 transcriptional co-activator.
MicroRNAs are small, non-coding RNAs that negatively regulate gene expression. It has been proposed that microRNAs could function in the regulation of innate immunity, but this has not been demonstrated for viral infection. Here we test this hypothesis using the human pathogenic virus Kaposi's sarcoma-associated herpesvirus (KSHV) and one of its putative natural cellular targets, primary lymphatic endothelial cells (LECs). We show that an early antiviral microRNA response (6 h post-infection) includes expression of microRNAs that enhance viral gene expression. In particular, the CREB-induced miR-132 microRNA is highly upregulated after infection and has a negative effect on the expression of interferon-stimulated genes, facilitating viral replication. We show a similar function for miR-132 during infection of monocytes with herpes simplex virus-1 (HSV-1) and human cytomegalovirus (HCMV). miR-132 regulates innate antiviral immunity by inhibiting expression of the p300 transcriptional co-activator. p300 is downregulated early after KSHV infection, and inhibition of miR-132 induction restores p300 expression. Furthermore, p300 regulates miR-132 levels, revealing a dynamic equilibrium between miR-132 and p300. By targeting p300, rather than a transcription factor or signalling protein, miR-132 has a broad role in the regulation of antiviral immunity.
Lagos
Dimitrios
D
Cancer Research UK Viral Oncology Group, UCL Cancer Institute, University College London, London WC1E 6BT, U.K.
Pollara
Gabriel
G
Henderson
Stephen
S
Gratrix
Fiona
F
Fabani
Martin
M
Milne
Richard S B
RS
Gotch
Frances
F
Boshoff
Chris
C
D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000276:immunology; D050881:E1A-Associated p300 Protein / Q000037:antagonists & inhibitors / Q000235:genetics*; D042783:Endothelial Cells / Q000276:immunology* / Q000821:virology; D005786:Gene Expression Regulation / Q000276:immunology*; D006564:Herpesviridae / Q000276:immunology*; D018259:Herpesvirus 1, Human / Q000276:immunology; D019288:Herpesvirus 8, Human / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D035683:MicroRNAs / Q000502:physiology*; D015854:Up-Regulation
C547077:MIRN132 microRNA, human; D035683:MicroRNAs; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human