Latency-associated nuclear antigen inhibits lytic replication of Kaposi's sarcoma-associated herpesvirus by regulating let-7a/RBPJ signaling

Abstract Latency-associated nuclear antigen (LANA) is the key factor in the establishment and maintenance of latency of Kaposi's sarcoma-associated herpesvirus (KSHV). A cellular protein, recombination signal binding protein for immunoglobulin kappa J region (RBPJ), is essential for the lytic reactivation of KSHV. However, whether RBPJ expression is regulated by KSHV is not clear. Here, we show that LANA upregulates let-7a and its primary transcripts in parallel with its reduction of RBPJ expression. An increase in notch intracellular domain (NICD) and the downregulation of NF-κB and LIN28B contribute to the upregulation of let-7a by LANA. Let-7a represses RBPJ expression by directly binding the 3′ untranslated region of RBPJ. Let-7a overexpression or RBPJ knockdown led to a dose- and time-dependent inhibition of lytic reactivation of KSHV. Collectively, these findings support a model wherein LANA inhibits the lytic replication of KSHV by regulating let-7a/RBPJ signaling.