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Journal of Virology, March 2008, p. 2792-2801, Vol. 82, No. 6
0022-538X/08/$08.00+0     doi:10.1128/JVI.01856-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Kaposi's Sarcoma-Associated Herpesvirus ORF57 Functions as a Viral Splicing Factor and Promotes Expression of Intron-Containing Viral Lytic Genes in Spliceosome-Mediated RNA Splicing{triangledown}

Vladimir Majerciak,1,{dagger} Koji Yamanegi,1,{dagger} Eric Allemand,2 Michael Kruhlak,3 Adrian R. Krainer,2 and Zhi-Ming Zheng1*

HIV and AIDS Malignancy Branch,1 Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892,3 Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 117242

Received 23 August 2007/ Accepted 20 December 2007

Kaposi's sarcoma-associated herpesvirus (KSHV) ORF57 facilitates the expression of both intronless viral ORF59 genes and intron-containing viral K8 and K8.1 genes (V. Majerciak, N. Pripuzova, J. P. McCoy, S. J. Gao, and Z. M. Zheng, J. Virol. 81:1062-1071, 2007). In this study, we showed that disruption of ORF57 in a KSHV genome led to increased accumulation of ORF50 and K8 pre-mRNAs and reduced expression of ORF50 and K-bZIP proteins but had no effect on latency-associated nuclear antigen (LANA). Cotransfection of ORF57 and K8β cDNA, which retains a suboptimal intron of K8 pre-mRNA due to alternative splicing, promoted RNA splicing of K8β and production of K8{alpha} (K-bZIP). Although Epstein-Barr virus EB2, a closely related homolog of ORF57, had a similar activity in the cotransfection assays, herpes simplex virus type 1 ICP27 was inactive. This enhancement of RNA splicing by ORF57 correlates with the intact N-terminal nuclear localization signal motifs of ORF57 and takes place in the absence of other viral proteins. In activated KSHV-infected B cells, KSHV ORF57 partially colocalizes with splicing factors in nuclear speckles and assembles into spliceosomal complexes in association with low-abundance viral ORF50 and K8 pre-mRNAs and essential splicing components. The association of ORF57 with snRNAs occurs by ORF57-Sm protein interaction. We also found that ORF57 binds K8β pre-mRNAs in vitro in the presence of nuclear extracts. Collectively our data indicate that KSHV ORF57 functions as a novel splicing factor in the spliceosome-mediated splicing of viral RNA transcripts.

* Corresponding author. Mailing address: HIV and AIDS Malignancy Branch, Center for Cancer Research, NCI/NIH, 10 Center Dr., Rm. 6N106, MSC-1868, Bethesda, MD 20892-1868. Phone: (301) 594-1382. Fax: (301) 480-8250. E-mail: zhengt{at}exchange.nih.gov

{triangledown} Published ahead of print on 9 January 2008.

{dagger} Both are first authors who contributed equally to this work.

Journal of Virology, March 2008, p. 2792-2801, Vol. 82, No. 6
0022-538X/08/$08.00+0     doi:10.1128/JVI.01856-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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