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Human herpesvirus 6B U19 protein is a PML-regulated transcriptional activator that localizes to nuclear foci in a PML-independent manner

¹ Institute of Medical Microbiology and Immunology, Bartholin Building, University of Aarhus, DK-8000 Aarhus C, Denmark
² Institute of Human Genetics, Bartholin Building, University of Aarhus, DK-8000 Aarhus C, Denmark

Correspondence
Per Höllsberg
ph{at}microbiology.au.dk

Human herpesvirus 6B (HHV-6B) contains an IE-B domain spanning open reading frames U16/17–U19, based on homology with human cytomegalovirus. Here, the protein product, U19, of the HHV-6B U19 gene is identified as a 47 kDa transcriptional activator. HHV-6B infection or overexpression of U19 transactivated the RANTES promoter. Mutational analysis of the promoter indicated that transactivation was not critically dependent on the promoter sites CRE, NF-B, ISRE or NF-IL6. ND10 are nuclear substructures that are involved in several cellular regulatory pathways, including those controlling gene expression. HHV-6B infection resulted in a reduced number of ND10 structures, but with a concomitantly increased level of promyelocytic leukaemia (PML) protein expression and mRNA induction. The U19 protein co-located to ND10 with PML and heterochromatin protein 1 (HP1), but whilst PML formed a ring structure, U19 also localized to the centre of ND10. Knockdown of PML by small interfering RNA did not prevent U19 localization to ND10-like foci, but instead led to a fourfold increase in U19-induced transcription from the RANTES promoter. Generation of four truncated U19 proteins indicated that the N-terminal portion of the protein contains a sequence responsible for nuclear localization; a domain in the N-terminal half of U19 is responsible for its ND10 localization, whereas the C-terminal portion contains the transactivation domain. None of the truncated proteins retained full transactivating ability on the RANTES promoter. Thus, U19 is a transcriptional activator that co-localizes with PML and localizes to ND10-like foci independently of PML, yet is regulated negatively by PML or its associated proteins.

A supplementary table showing primers used for PCR, real-time PCR and sequencing is available with the online version of this paper.