miR-132 regulates antiviral innate immunity through suppression of the p300 transcriptional co-activator

Dimitrios Lagos, et al. Nature Cell Biology 12, 513 – 519 (2010)

Speaker: Wei-Min Hung (洪偉珉)                                 Time: 13：10 ~ 14：00, Nov. 17, 2010

Commentator: Dr. Hsiao-Sheng Liu (劉校生 老師)     Place: Room 601

Abstract:

microRNA (miRNA, miR) is an endogenous non-coding RNA on average only 22 nucleotides. miRNA can bind to complementary sequences in the 3’ untranslated regions (3' UTRs) of target messenger RNA transcripts (mRNAs), usually resulting in gene silencing.  Previous studies revealed that miRNA may function in innate immunity by suppressing the inflammatory response. However, this concept has not been validated in the interferon (IFN) response to viral infection. The authors therefore aimed to determine the role of host miRNAs in the innate immune response by using the human pathogenic virus Kaposi’s sarcoma-associated herpesvirus (KSHV) and one of its putative natural cellular targets, primary lymphatic endothelial cells. The result showed that miRNA miR-132 was induced after early KSHV infection to inhibit the antiviral interferon response and to enhance viral gene expression. In particular, miR-132 was induced through a CREB (cAMP response element binding protein)-dependent mechanism and was highly up-regulated after infection. miR-132 had a negative effect on the expression of interferon-stimulated genes, facilitating viral replication. Similar function of miR-132 was observed for both herpes simplex virus-1 and human cytomegalovirus infection of monocytes. miR-132 regulates innate antiviral immunity by inhibiting expression of the p300 transcriptional co-activator. p300 is a target of miR-132 and is down-regulated after early KSHV infection. However, p300 can also regulate miR-132 levels, revealing a dynamic equilibrium between miR-132 and p300. In summary, the authors revealed a viral gene expression-independent, host-miRNA-mediated and p300-specific mechanism that regulates the interferon response.

References:

1. Baltimore, D., et al. MicroRNAs: new regulators of immune cell development and function. Nat. Immunol. 9, 839–845 (2008).

2. Taganov, K. D., et al. NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc. Natl Acad. Sci. USA 103, 12481–12486 (2006).

3. Mayr, B. & Montminy, M. Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat. Rev. Mol. Cell Biol. 2, 599–609 (2001).