Convergence of Kaposi's sarcoma-associated herpesvirus reactivation with Epstein-Barr virus latency and cellular growth mediated by the notch signaling pathway in coinfected cells.
Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of primary effusion lymphoma (PEL). All PEL cell lines are infected with KSHV, and 70% are coinfected with Epstein-Barr virus (EBV). KSHV reactivation from latency requires promoter-specific transactivation by the KSHV Rta protein through interactions with RBP-Jk (CSL), the cellular DNA-binding component of the Notch signal transduction pathway. EBV transformation of primary B cells requires EBV nuclear antigen 2 (EBNA-2) to interact with RBP-Jk to direct the latent viral and cellular gene expression program. Although KSHV Rta and EBV EBNA-2 both require RBP-Jk for transactivation, previous studies have suggested that RBP-Jk-dependent transactivators do not function identically. We have found that the EBV latent protein LMP-1 is expressed in less than 5% of KSHV(+)/EBV(+) PEL cells but is induced in an Rta-dependent fashion when KSHV reactivates. KSHV Rta transactivates the EBV latency promoters in an RBP-Jk-dependent fashion and forms a ternary complex with RBP-Jk on the promoters. In B cells that are conditionally transformed by EBV alone, we show that KSHV Rta complements a short-term EBNA-2 growth deficiency in an autocrine/paracrine manner. Complementation of EBNA-2 deficiency by Rta depends on RBP-Jk and LMP-1, and Rta transactivation is required for optimal growth of KSHV(+)/EBV(+) PEL lines. Our data suggest that Rta can contribute to EBV-driven cellular growth by transactivating RBP-Jk-dependent EBV latency genes. However, our data also suggest that EBNA-2 and Rta induce distinct alterations in the cellular proteomes that contribute to the growth of infected cells.
Spadavecchia
Sophia
S
Department of Microbiology and Molecular Genetics and Graduate School of Biomedical Sciences, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey 07103, USA.
Gonzalez-Lopez
Olga
O
Carroll
Kyla Driscoll
KD
Palmeri
Diana
D
Lukac
David M
DM
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D049109:Cell Proliferation; D017077:Culture Media, Conditioned; D017931:DNA Primers / Q000235:genetics; D019309:Epstein-Barr Virus Nuclear Antigens / Q000235:genetics / Q000502:physiology; D015870:Gene Expression; D005814:Genes, Viral; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D054884:Host-Pathogen Interactions / Q000502:physiology; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000502:physiology; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D011401:Promoter Regions, Genetic; D051880:Receptors, Notch / Q000502:physiology*; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology; D014162:Transfection; D014763:Viral Matrix Proteins / Q000235:genetics / Q000502:physiology; D014764:Viral Proteins / Q000235:genetics / Q000502:physiology; D014775:Virus Activation / Q000502:physiology
D017077:Culture Media, Conditioned; D017931:DNA Primers; C402641:EBNA-2 protein, Human herpesvirus 4; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D019309:Epstein-Barr Virus Nuclear Antigens; D017874:Immediate-Early Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D051880:Receptors, Notch; C417604:Rta protein, Human herpesvirus 8; D015534:Trans-Activators; D014763:Viral Matrix Proteins; D014764:Viral Proteins