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Molecular and Cellular Biology, April 2002, p. 2136-2146, Vol. 22, No. 7
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.7.2136-2146.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Protein Kinase A Associates with HA95 and Affects Transcriptional Coactivation by Epstein-Barr Virus Nuclear Proteins

Innoc Han,1,2 Yong Xue,2 Shizuko Harada,2 Sigurd Orstavik,3 Bjorn Skalhegg,3 and Elliott Kieff2*

Ewha Institute of Neuroscience, Ewha University Medical School, Seoul 110-783, Korea,1 Program in Virology and Departments of Medicine and Microbiology and Molecular Genetics, Channing Laboratory, Brigham and Women's Hospital and Harvard University, Boston, Massachusetts,2 Institute of Medical Biochemistry, University of Oslo, 0317 Oslo, Norway3

Received 28 June 2001/ Returned for modification 10 August 2001/ Accepted 1 January 2002

HA95, a nuclear protein homologous to AKAP95, has been identified in immune precipitates of the Epstein-Barr virus (EBV) coactivating nuclear protein EBNA-LP from EBV-transformed lymphoblastoid cells (LCLs). We now find that HA95 and EBNA-LP are highly associated in LCLs and in B-lymphoma cells where EBNA-LP is expressed by gene transfer. Binding was also evident in yeast two-hybrid assays. HA95 binds to the EBNA-LP repeat domain that is the principal coactivator of transcription. EBNA-LP localizes with HA95 and causes HA95 to partially relocalize with EBNA-LP in promyelocytic leukemia nuclear bodies. Protein kinase A catalytic subunit {alpha} (PKAcs{alpha}) is significantly associated with HA95 in the presence or absence of EBNA-LP. Although EBNA-LP is not a PKA substrate, HA95 or PKAcs{alpha} expression in B lymphoblasts specifically down-regulates the strong coactivating effects of EBNA-LP. The inhibitory effects of PKAcs{alpha} are reversed by coexpression of protein kinase inhibitor. PKAcs{alpha} also inhibits EBNA-LP coactivation with the EBNA-2 acidic domain fused to the Gal4 DNA binding domain. Furthermore, EBNA-LP- and EBNA-2-induced expression of the EBV oncogene, LMP1, is down-regulated by PKAcs{alpha} or HA95 expression in EBV-infected lymphoblasts. These experiments indicate that HA95 and EBNA-LP localize PKAcs{alpha} at nuclear sites where it can affect transcription from specific promoters. The role of HA95 as a scaffold for transcriptional regulation is discussed.

* Corresponding author. Mailing address: Program in Virology and Departments of Medicine and Microbiology and Molecular Genetics, Channing Laboratory, Brigham and Women's Hospital and Harvard University, 181 Longwood Ave., Boston, MA 02115. Phone: (617) 525-4252. Fax: (617) 525-4257. E-mail: ekieff{at}rics.bwh.harvard.edu.

Molecular and Cellular Biology, April 2002, p. 2136-2146, Vol. 22, No. 7
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.7.2136-2146.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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