title: Kaposi's sarcoma-associated herpesvirus K8beta is derived from a spliced intermediate of K8 pre-mRNA and antagonizes K8alpha (K-bZIP) to induce p21 and p53 and blocks K8alpha-CDK2 interaction.
abstract: 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 beta, by inclusion (beta) 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 beta-globin intron into the K8beta exon 3-exon 4 splice junction, which promoted splicing of K8beta intron 2 and conversion of the K8beta mRNA to the K8alpha mRNA that encodes a K-bZIP protein. Intron 2 contains a premature termination codon, yet the K8beta mRNA is insensitive to nonsense-mediated mRNA decay, suggesting that the truncated K8beta protein may have a biological function. Indeed, although the truncated K8beta 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 K8alpha mRNA production.
authors.affiliation: HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-1868, USA.
authors.forename: Koji
authors.initials: K
authors.lastname: Yamanegi
authors.forename: Shuang
authors.initials: S
authors.lastname: Tang
authors.forename: Zhi-Ming
authors.initials: ZM
authors.lastname: Zheng
mesh_terms: D017398:Alternative Splicing; D001402:B-Lymphocytes / Q000821:virology; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D015967:Gene Expression Regulation, Viral; D006367:HeLa Cells; D019288:Herpesvirus 8, Human / Q000235:genetics*; D006801:Humans; D007438:Introns / Q000235:genetics; D007668:Kidney; D010957:Plasmids; D012322:RNA Precursors / Q000235:genetics*; D012367:RNA, Viral / Q000235:genetics*; D016914:Ribonuclease H; D014162:Transfection
chemical_list: D017931:DNA Primers; D012322:RNA Precursors; D012367:RNA, Viral; D016914:Ribonuclease H