Notch signal transduction induces a novel profile of Kaposi's sarcoma-associated herpesvirus gene expression.
Kaposi's sarcoma-associated herpesvirus (KSHV) RTA transcription factor is recruited to its responsive elements through interaction with RBP-Jkappa that is a downstream transcription factor of the Notch signaling pathway that is important in development and cell fate determination. This suggests that KSHV RTA mimics cellular Notch signal transduction to activate viral lytic gene expression. Here, I demonstrated that unlike other B lymphoma cells, KSHV-infected primary effusion lymphoma BCBL1 cells displayed the constitutive activation of ligand-mediated Notch signal transduction, evidenced by the Jagged ligand expression and the complete proteolytic process of Notch receptor I. In order to investigate the effect of Notch signal transduction on KSHV gene expression, human Notch intracellular (hNIC) domain that constitutively activates RBP-Jkappa transcription factor activity was expressed in BCBL1 cells, TRExBCBL1-hNIC, in a tetracycline inducible manner. Gene expression profiling showed that like RTA, hNIC robustly induced expression of a number of viral genes including K5 immune modulatory gene resulting in downregulation of MHC I and CD54 surface expression. Finally, the genetic analysis of KSHV genome demonstrated that the hNIC-mediated expression of K5 during viral latency consequently conferred the downregulation of MHC I and CD54 surface expression. These results indicate that cellular Notch signal transduction provides a novel expression profiling of KSHV immune deregulatory gene that consequently confers the escape of host immune surveillance during viral latency.
Chang
Heesoon
H
Department of Microbiology and Molecular Genetics and Tumor Virology Division, New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts 01772, USA. heesoon_chang@hms.harvard.edu
D000954:Antigens, Surface / Q000032:analysis; D002478:Cells, Cultured; D015536:Down-Regulation; D020869:Gene Expression Profiling; D015967:Gene Expression Regulation, Viral; D005814:Genes, Viral / Q000235:genetics; D019288:Herpesvirus 8, Human / Q000235:genetics*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics*; D008214:Lymphocytes / Q000276:immunology; D017434:Protein Structure, Tertiary; D051880:Receptors, Notch / Q000378:metabolism*; D012514:Sarcoma, Kaposi / Q000821:virology; D015398:Signal Transduction; D014764:Viral Proteins / Q000235:genetics*
D000954:Antigens, Surface; D017874:Immediate-Early Proteins; C405867:K5 protein, Human herpesvirus 8; D051880:Receptors, Notch; D014764:Viral Proteins