| The forkhead box 0 (FOXO) transcription factor family has been shown to play important and diverse roles in many biological processes, such as cell proliferation, cell death, metabolism, and stress responses. It has also been shown to participate in key steps of the virus life cycle, as well as in the pathogenesis of gamma herpesvirus, hepatitis C virus, and human immunodeficiency virus. In this report, we found that human cytomegalovirus (HCMV) could dramatically induce the expression of FOXO1 during its infection of human fibroblasts. The Immunofluorescence results showed that the induced FOXO1 was recruited to the viral replication compartments (vRC) in the nucleus, where it co-localized with the typical vRC component pUL44. This indicated that HCMV not only induced expression of FOXO1 but also promoted its accumulation in viral replication compartment. To further investigate the importance of FOXO1 for HCMV infection, the expression of FOXO1 was suppressed by RNA interference which significantly inhibited HCMV replication and the production of progeny virus was reduced by about 60-fold. To explain why FOXO1 is so important for HCMV infection, we detected the expression of viral immediate early, early, and late genes expression during the course of HCMV infection, the result revealed that FOXO1 knockdown intensively crippled viral late gene expression at the transcriptional level. In addition, suppression of FOXO1 expression in virus-infected cells would cause a 3-fold inhibition of viral DNA synthesis. Intriguingly, the expression of superoxide dismutase 2 (SOD2) and Catalase, two canonical FOXO target genes, was suppressed as opposed to induced during HCMV infection, regardless of high FOXO1 expression. Forced expression of SOD2 and catalase impaired HCMV replication. These results indicated an especially important role of FOXO1 in HCMV replication, highlighting the attractive idea of antagonizing FOXO1 as a potential drug target against HCMV infection. |
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