Regulation of NF-kappaB inhibitor IkappaBalpha and viral replication by a KSHV microRNA.

Nat Cell Biol 2010 Feb 17;12(2):193-9. Epub 2010 Jan 17.

Tumor Virology Program, Greehey Children's Cancer Research Institute, and Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.

Kaposi's sarcoma-associated herpesvirus (KSHV) is causally linked to several acquired immune deficiency syndrome-related malignancies, including Kaposi's sarcoma, primary effusion lymphoma (PEL) and a subset of multicentric Castleman's disease. Control of viral lytic replication is essential for KSHV latency, evasion of the host immune system and induction of tumours. Here, we show that deletion of a 14 microRNA (miRNA) cluster from the KSHV genome significantly enhances viral lytic replication as a result of reduced NF-kappaB activity. The miRNA cluster regulates the NF-kappaB pathway by reducing expression of IkappaBalpha protein, an inhibitor of NF-kappaB complexes. Computational and miRNA seed mutagenesis analyses were used to identify KSHV miR-K1, which directly regulates the IkappaBalpha protein level by targeting the 3'UTR of its transcript. Expression of miR-K1 is sufficient to rescue NF-kappaB activity and inhibit viral lytic replication, whereas inhibition of miR-K1 in KSHV-infected PEL cells has the opposite effect. Thus, KSHV encodes an miRNA to control viral replication by activating the NF-kappaB pathway. These results demonstrate an important role for KSHV miRNAs in regulating viral latency and lytic replication by manipulating the host survival pathway.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2815189PMC
February 2010
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References

(Supplied by CrossRef)
Article in Annu. Rev. Pathol.
D Ganem et al.
Annu. Rev. Pathol. 2006
Article in Proc. Natl Acad. Sci. USA
X Cai et al.
Proc. Natl Acad. Sci. USA 2005
Article in Nature Methods
S Pfeffer et al.
Nature Methods 2005
Article in J. Virol.
MA Samols et al.
J. Virol. 2005
Article in RNA
A Grundhoff et al.
RNA 2006
Article in PLoS Pathog.
AJ O'Hara et al.
PLoS Pathog. 2009
Article in Nature
E Gottwein et al.
Nature 2007
Article in J. Virol.
RL Skalsky et al.
J. Virol. 2007
Article in PLoS Pathog.
MA Samols et al.
PLoS Pathog. 2007
Article in Nature Genet.
JM Ziegelbauer et al.
Nature Genet. 2009
Article in Cell Host Microbe
D Nachmani et al.
Cell Host Microbe 2009

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