Kaposi sarcoma-associated herpesvirus latency-associated nuclear antigen inhibits interferon (IFN) beta expression by competing with IFN regulatory factor-3 for binding to IFNB promoter.
Host cells respond to viral infections by synthesizing and producing antiviral molecules such as type I interferons (IFN). The Kaposi sarcoma-associated herpesvirus (KSHV) encodes multiple proteins expressed during the lytic replication cycle that alter the antiviral response of the host. Considering that in Kaposi sarcoma lesions and primary effusion lymphoma cells KSHV is latent in the vast majority of cells, we were interested in determining whether latently expressed viral proteins have the ability to modulate IFN synthesis. The latency-associated nuclear antigen (LANA-1) is a large nuclear protein that plays a role in the establishment and maintenance of latent KSHV episome in the nucleus of infected cells. LANA-1 is also described to modulate the cellular transcription. Here, we report that LANA-1 inhibits IFN-beta transcription and synthesis by competing with the binding of interferon regulatory factor-3 (IRF3) to the IFNB promoter. Using mutants of LANA-1, we have identified the central acidic repeated region as the domain essential for interfering with the binding of IRF3 to the positive regulatory domains I-III of the IFNB promoter. In addition, the nuclear localization of LANA-1 proved essential for IFN-beta inhibition. Thus, LANA-1 interferes with the formation of IFN-beta enhanceosome by competing with the fixation of IRF3 and by inhibiting the expression of the CREB-binding protein. The ability of LANA-1 to inhibit IFNB gene expression highlights a new role for this protein in cellular gene modulation and immune evasion strategies.
Cloutier
Nathalie
N
Laboratory of Virology, Rheumatology and Immunology Research Center, Centre Hospitalier Universitaire de Québec Research Center and Faculty of Medicine, Laval University, Québec City, Québec G1V 4G2, Canada.
Flamand
Louis
L
D000818:Animals; D000956:Antigens, Viral / Q000235:genetics / Q000378:metabolism*; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism*; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012514:Sarcoma, Kaposi / Q000821:virology; D017735:Virus Latency
D000956:Antigens, Viral; D017362:Cyclic AMP Response Element-Binding Protein; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D009687:Nuclear Proteins; C109540:latency-associated nuclear antigen; D016899:Interferon-beta; D050882:CREB-Binding Protein; C494363:CREBBP protein, human