Silence Blog

HOT paper: Mature and functional viral miRNAs transcribed from novel RNA polymerase III promoters

Viruses take advantage of the host cell machinery to replicate their genome and produce more viral particles. Viruses are known to evolve rapidly and find novel ways to take advantage of existing cellular machinery to propagate. For example, Hepatitis C virus (HCV) utilizes signaling pathways such as epidermal growth factor-receptor pathway, the PI3K/Akt cascade or Src kinase-dependent pathways (Bode et al. 2009).

The miRNA pathway is no exception to this phenomenon. Previously, viruses were demonstrated to have miRNA genes (Pfeffer et al. 2005, 2004; Gottwein and Cullen 2008; Cullen 2009).

In this paper, Diebel KW. and colleagues reported the existence of Murid herpesvirus 4 (MUHV-4) microRNAs  in lytically infected cells and infected tissues samples ex vivo. For the first time, they could detect gHV68 pri-miRNAs, processed intermediates and mature miRNAs existing in lytically infected cells. Authors not only report the existence of these miRNAs and their precursors in lytically infected cells, but they also confirm that these miRNAs are  functional by using a luciferase reporter system in the infected cells.

Unlike the previously reported mature miRNAs from Epstein-Barr virus (EBV) and Kaposi’s sarcoma- associated herpesvirus (KSHV), that are processed from  RNA-pol II transcribed pri-miRNAs, the precursors of the miRNAs from MUHV-4  seem to be transcribed by RNA pol III.   In fact, MuvHV-4 is the only herpesvirus examined to date that has been predicted to generate its pri-miRNA transcript through RNA polymerase III (pol III) transcription.

Most of the human miRNAs are transcribed by RNA pol II; and some miRNAs genes that are interspersed among Alu repeats require RNA pol III for transcription(Borchert et al. 2006).  The transcription of these miRNA precursors, but not control pol-II dependent transcripts, are -amanitin sensitive, suggesting that they don't require RNA pol II for transcription.  Furthermore, the specific deletion of the RNA polymerase III promoter elements of MuvHV-4 result in the complete loss of miRNA detection.  Some future experiments such as ChIPs using antibodies specific for RNA pol III might also be done to  address direct interaction of RNA pol III with the RNA polymerase III promoter elements of MuvHV-4.

In summary, the authors  propose the existence of novel viral transcripts that are transcribed by RNA pol III  and  are processed by cellular RNAse III enzymes to produce functional mature viral miRNAs.  Further sequencing and functional studies with infected cells might reveal more virally expressed miRNAs.

A deeper understanding of viral miRNAs may provide the basis for novel therapies to combat viruses (Bode et al. 2009).

Elif Sarinay
 
References:
 
1) Bode JG, Brenndorfer ED, Karthe J, Haussinger D. Interplay between host cell and hepatitis C virus in regulating viral replication. Biol Chem. 2009 Oct;390(10):1013-32.

2) Pfeffer S, et al. Identification of microRNAs of the herpesvirus family. Nat Methods. 2005 Apr;2(4):269-76. Epub 2005 Feb 16.

3) Gottwein E, Cullen BR. Viral and cellular microRNAs as determinants of viral pathogenesis and immunity. Cell Host Microbe. 2008 Jun 12;3(6):375-87.

4) Umbach JL, Cullen BR. The role of RNAi and microRNAs in animal virus replication and antiviral immunity. Genes Dev. 2009 May 15;23(10):1151-64.

5) Kevin W. Diebel, Anna L. Smith and Linda F. van Dyk. Mature and functional viral miRNAs transcribed from novel RNA  polymerase III promoters. RNA 2010 16(1):170-85

6) Borchert et al. RNA polymerase transcribes human microRNAs. Nature Structural & Molecular Biology 2006 13(12):1097-101.

Posted by Elif Sarinay at 06:43    Comments (0)