Carboxy terminus of human herpesvirus 8 latency-associated nuclear antigenmediates dimerization, transcriptional repression, and targeting to nuclear bodies

Human herpesvirus 8 (HHV-8; also known as Kaposi's sarcoma-associated herpe svirus) is the causative agent of Kaposi's sarcoma and certain B-cell lymph omas, In most infected cells, HHV-8 establishes a latent infection characte rized by the expression of latency-associated nuclear antigen (LANA) encode d by open reading frame 73. Although unrelated by sequence, there are funct ional similarities between LANA and the EBNA-1 protein of Epstein-Barr viru s. Both accumulate as subnuclear speckles and are required for maintenance of the viral episome, EBNA-1 also regulates viral gene expression and is re quired for cell immortalization, suggesting that LANA performs similar func tions in the context of HHV-8 infection, Here we show that LANA forms stabl e dimers, or possibly higher-order multimers, and that this is mediated by a conserved region in the C terminus. By expressing a series of truncations , we show that both the N- and C-terminal regions localize to the nucleus, although only the C terminus accumulates as nuclear speckles characteristic of the intact protein. Lastly, we show that LANA can function as a potent transcriptional repressor when tethered to constitutively active promoters via a heterologous DNA-binding domain. Domains in both the N and C termini mediate repression. This suggests that one function of LANA is to suppress the expression of the viral lytic genes or cellular genes involved in the a ntiviral response.