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Journal of Virology, November 2005, p. 14207-14221, Vol. 79, No. 22
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.22.14207-14221.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Kaposi's Sarcoma-Associated Herpesvirus K8ß Is Derived from a Spliced Intermediate of K8 Pre-mRNA and Antagonizes K8{alpha} (K-bZIP) To Induce p21 and p53 and Blocks K8{alpha}-CDK2 Interaction

Koji Yamanegi, Shuang Tang, and Zhi-Ming Zheng*

HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892

Received 12 March 2005/ Accepted 22 August 2005

Kaposi's sarcoma-associated herpesvirus (KSHV) is a lymphotropic DNA tumor virus that induces Kaposi's sarcoma and AIDS-related primary effusion lymphoma. KSHV open reading frame 50 and K8 genes in early viral lytic infection express, respectively, a tricistronic and a bicistronic pre-mRNA, which undergo alternative splicing to create two major spliced mRNA isoforms, {alpha} and ß, by inclusion (ß) or exclusion ({alpha}) of an intron at nucleotides 75563 to 75645. This intron contains some suboptimal features, which cause the intron 5' splice site (ss) to interact weakly with U1 snRNA and the 3' ss to bind a U2 auxiliary factor, U2AF, with low affinity. Optimization of this intron in K8 (K8 intron 2) promoted the interaction of the 5' ss with U1 and the 3' ss with U2AF, resulting in a substantial increase in intron splicing. Splicing of K8 intron 2 has also been shown to be stimulated by the splicing of a downstream intron. This was confirmed by the insertion of a human ß-globin intron into the K8ß exon 3-exon 4 splice junction, which promoted splicing of K8ß intron 2 and conversion of the K8ß mRNA to the K8{alpha} mRNA that encodes a K-bZIP protein. Intron 2 contains a premature termination codon, yet the K8ß mRNA is insensitive to nonsense-mediated mRNA decay, suggesting that the truncated K8ß protein may have a biological function. Indeed, although the truncated K8ß protein is missing only a C-terminal leucine zipper domain from the K-bZIP, its expression antagonizes the ability of the K-bZIP to induce p53 and p21 and blocks K-bZIP-CDK2 interaction through interfering K8{alpha} mRNA production.

* Corresponding author. Mailing address: HIV and AIDS Malignancy Branch, Center for Cancer Research, NCI/NIH, 10 Center Dr., Rm. 10 S255, MSC-1868, Bethesda, MD 20892-1868. Phone: (301) 594-1382. Fax: (301) 480-8250. E-mail: zhengt{at}exchange.nih.gov.

Journal of Virology, November 2005, p. 14207-14221, Vol. 79, No. 22
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.22.14207-14221.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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