Kaposi's sarcoma-associated herpesvirus viral interferon regulatory factor 4 (vIRF4) targets expression of cellular IRF4 and the Myc gene to facilitate lytic replication.

[primary effusion lymphoma]

Besides an essential transcriptional factor for B cell development and function , cellular interferon regulatory factor 4 (c-IRF 4 ) directly regulates expression of the c-Myc gene , which is not only associated with various B cell lymphomas but also required for herpesvirus latency and pathogenesis . Kaposi 's sarcoma -associated herpesvirus (KSHV ), the etiological agent of Kaposi 's sarcoma and primary effusion lymphoma , has developed a unique mechanism to deregulate host antiviral innate immunity and growth control by incorporating four viral homologs (vIRF 1 to -4 ) of cellular IRFs into its genome . Previous studies have shown that several KSHV latent proteins , including vIRF 3 , vFLIP , and LANA , target the expression , function , and stability of c-Myc to establish and maintain viral latency . Here we report that the KSHV vIRF 4 lytic protein robustly suppresses expression of c-IRF 4 and c-Myc , reshaping host gene expression profiles to facilitate viral lytic replication . Genomewide gene expression analysis revealed that KSHV vIRF 4 grossly affects host gene expression by upregulating and downregulating 118 genes and 166 genes , respectively , by at least 2 -fold . Remarkably , vIRF 4 suppressed c-Myc expression by 11 -fold , which was directed primarily by the deregulation of c-IRF 4 expression . Real-time quantitative PCR (RT-qPCR ), single -molecule in situ hybridization , and chromatin immunoprecipitation assays showed that vIRF 4 not only reduces c-IRF 4 expression but also competes with c-IRF 4 for binding to the specific promoter region of the c-Myc gene , resulting in drastic suppression of c-Myc expression . Consequently , the loss of vIRF 4 function in the suppression of c-IRF 4 and c-Myc expression ultimately led to a reduction of KSHV lytic replication capacity . These results indicate that the KSHV vIRF 4 lytic protein comprehensively targets the expression and function of c-IRF 4 to downregulate c-Myc expression , generating a favorable environment for viral lytic replication . Finally , this study further reinforces the important role of the c-Myc gene in KSHV lytic replication and latency .

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Diseases presenting "pathogenesis" symptom

erythropoietic protoporphyria

primary effusion lymphoma

typhoid

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