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It is still largely unknown what host factors are involved in controlling the expression of the lytic viral gene RTA during primary infection, which determines if Kaposi's sarcoma-associated herpesvirus (KSHV) establishes latent or lytic infection. We have recently identified the histone demethylase KDM2B as a repressor of RTA expression during both de novo KSHV infection and latency based on an epigenetic factor siRNA screen. Here, we report that surprisingly, KDM2B overexpression can promote lytic de novo infection by using a mechanism that differs from what is needed for its repressor function. Our study revealed that while the DNA-binding and demethylase activities of KDM2B linked to its transcription repressive function are dispensable, its C-terminal F-box and LRR domains are required for the lytic infection-inducing function of KDM2B. We found that overexpressed KDM2B increases the half-life of the AP-1 subunit c-Jun protein and induces the AP-1 signaling pathway. This effect is dependent upon the binding of KDM2B to the SKP1-CUL1-F-box (SCF) E3 ubiquitin ligase complex via its F-box domain. Importantly, the inhibition of AP-1 reduces KDM2B-mediated lytic de novo KSHV infection. Overall, our findings indicate that KDM2B may induce the degradation of some host factors by using the SCF complex resulting in the enrichment of c-Jun. This leads to increased AP-1 transcriptional activity, which facilitates lytic gene expression following de novo infection interfering with the establishment of viral latency. Significance The expression of epigenetic factors is often dysregulated in cancers or upon specific stress signals, which often results in a display of non-canonical functions of the epigenetic factors that are independent from their chromatin-modifying roles. We have previously demonstrated that KDM2B normally inhibits KSHV lytic cycle using its histone demethylase activity. Surprisingly, we found that KDM2B overexpression can promote lytic de novo infection, which does not require its histone demethylase or DNA-binding functions. Instead, KDM2B uses the SKP1-CUL1-F-box (SCF) E3 ubiquitin ligase complex to induce AP-1 transcriptional activity, which promotes lytic gene expression. This is the first report that demonstrates a functional link between SFC KDM2B and AP-1 in the regulation of KSHV lytic cycle.

journal of virology

KDM2B Overexpression Facilitates Lytic <i>De Novo</i> Kaposi's Sarcoma-Associated Herpesvirus Infection by Inducing AP-1 Activity through Interaction with the SCF E3 Ubiquitin Ligase Complex

KDM2B Overexpression Facilitates Lytic De Novo Kaposi's Sarcoma-Associated Herpesvirus Infection by Inducing AP-1 Activity through Interaction with the SCF E3 Ubiquitin Ligase Complex