Suppression of microRNA-silencing pathway by HIV-1 during virus replication

Sciences 315:1579-1582 (2007)

Speaker: 王莉萩                             Time: 13:00 – 14:00, Oct. 31, 07

Commentator:王憲威 老師             Room: 601

        MicroRNAs are a class of small non-coding RNA modulating gene expression at post-transcriptional level, and are vital components of the innate antiviral responses. MicroRNAs are transcripted by RNA polymerase II, cleaved by Drosha and Dicer, incorporated into the RNA-induced silencing complex (RISC), and finally degraded the target mRNA or inhibited its translation. In this paper, the authors wanted to know whether the microRNA-silencing machinery influences HIV-1 replication. Knockdown of endogenous Dicer and Drosha expression using specific small interfering RNA increased HIV-1 replication in the peripheral mononuclear cells, indicating that Dicer and Drosha mediate the inhibition of HIV-1 replication. In HIV-1 infected cells, the polycistronic microRNA cluster, miR17/92, which encodes miR17-(5p/3p), miR-18, miR-19a, miR-19b-1, miR-20a, and miR-92-1, was downregulated. Subsequently, the authors found that miR-17-5p and miR-20a targeted to a cellular protein, PCAF, which is a cofactor for Tat transactivation of an integrated HIV-1. Knocking down the expression of miR-17-5p and miR-20a increased HIV-1 replication, and similar results were observed in the PCAF knockdown cells. In addition, miR-17-5p and miR-20a targeted to the 3’-untranslated region of PCAF mRNA and inhibited the translation of the PCAF mRNA rather than degrading it. In the Dicer or Drosha knockdown cells, knockdown of PCAF expression inhibited HIV-1 replication. In conclusion, miR-17-5p and miR-20a, synthesized by Dicer and Drosha, inhibit HIV-1 replication by decreasing the expression of Tat cofactor, PCAF.

References

1.         Dykxhoorn, D. M., C. D. Novina, and P. A. Sharp. 2003. Killing the messenger: short RNAs that silence gene expression. Nat Rev Mol Cell Biol 4:457-67.

2.         Sarnow, P., C. L. Jopling, K. L. Norman, S. Schutz, and K. A. Wehner. 2006. MicroRNAs: expression, avoidance and subversion by vertebrate viruses. Nat Rev Microbiol 4:651-9.