RSK-c-Fos in KSHV lytic progression

Kaposi’s sarcoma (KS) is a common malignancy in untreated AIDS patients that is caused by the infection of Kaposi’s sarcoma-associated herpesvirus (KSHV). KS lesions are characterized by spindle-shaped endothelial cells with infiltration of inflammatory cells and neoangiogenesis. KSHV commonly establishes default latent infection, but lytic replications occur in a small fraction of cells and play critical roles in KS pathogenesis by serving as a reservoir of infectious virion for persistent infection and inducing continuous paracrine factors for tumor progression. KSHV lytic infection triggers a variety of cellular machinery for replication and remodels cellular transcriptome. Distinct transcriptional patterns are exhibited in the immediate early (IE) and late stages of lytic replication. Previous studies have revealed that multiple pathways activate IE gene expression during lytic infection and reactivation from latency. However, the mechanism of late lytic gene expression regulation has remained largely undefined for a long time. Recently, studies have revealed that both host and viral factors, ORF45-prolonged c-Fos and TATA box binding protein (TBP)-like protein ORF24, are required for late lytic transcription [1, 2]. Our previous observations demonstrated that KSHV tegument protein ORF45 interacts with p90 ribosomal S6 protein kinase (RSK) and induces reciprocal ERK-RSK activation through the formation of ORF45-ERK-RSK multiprotein complexes that protect active ERK-RSK from dephosphorylation, consequently activating a sustained ERK-MAPK cascade that is essential for lytic replication [3, 4]. Deficiency of sustained ERK-RSK activation by ORF45-null or ORF45-F66A point mutagenesis significantly reduces the late lytic gene expression and progeny virion yield[5], indicating the essential role of ORF45-mediated sustained ERK-RSK activation during late lytic replication. This sustained signaling phosphorylates eukaryotic translation initiation factor eIF4B and therefore facilitates translation and promotes virion production [6]. Our latest studies have further revealed that sustained activation of this pathway prolongs c-Fos accumulation and activation to accelerate viral lytic transcription during the late stage of lytic replication [1], providing the evidence that ORF45-mediated sustained ERK-RSK activation promotes viral lytic replication at both the transcription and translation levels (Figure 1). As the sensor of sustained ERK-RSK activation, Editorial