A complex translational program generates multiple novel proteins from thelatently expressed kaposin (K12) locus of Kaposi's sarcoma-associated herpesvirus

The most abundantly expressed latent transcripts encoded by the Kaposi's sa rcoma (KS)-associated herpesvirus derive from the genomic region surroundin g open reading frame (ORF) K12 (kaposin A). Here we show that these transcr ipts, initially described as limited to ORF K12 itself, more frequently enc ompass upstream sequences spanning two sets of 23-nucleotide GC-rich direct repeats (DRs) (DR1 and DR2). Although the DRs lack AUG codons and were pre viously presumed to be noncoding, a monoclonal antibody raised to infected cells detected multiple polypeptides encoded by this region. These proteins are expressed during latency and upon induction of lytic viral replication in both primary effusion lymphoma (FEL) cell lines and KS tumors. Biochemi cal and genetic analyses reveal that these proteins are derived from varian t translational initiation at CUG codons. The predominant translation produ ct in the PEL cell line BCBL-1, derives from the 5'-most CUG codon in the t ranscript., resulting in a protein (termed kaposin B) which is encoded larg ely by the repeats themselves and which does not include K12 sequences. Oth er non-AUG codons in alternate reading frames are also used at lower effici ency, including one that initiates translation of a DR-K12 fusion protein ( kaposin C) that is predicted to sort to a different subcellular locale than kaposin B, Thus, the products of the K12 region, which is the most abundan tly transcribed region in latency, are surprisingly complex and may encompa ss multiple biological functions.