Suppression of KSHV lytic replication and primary effusion lymphoma by selective RNF5 inhibition

Author summaryPrimary effusion lymphoma is a rare malignant B-cell lymphoma with multifarious gene mutations and genomic abnormalities, and is tightly associated with KSHV infection; currently, no effective therapy for PEL has been established. RNF5 regulates autophagy, antiviral and antitumor immunity, inflammation and metabolism, which are important for tumorigenesis. However, whether RNF5 acts as a therapeutic target for viral infection or cancer chemotherapy remains unclear. Here, we demonstrated that RNF5 inhibition suppresses PEL xenograft tumor growth and oncogenic KSHV lytic replication through increased EphA3 and EphA4 levels and decreased downstream pathways. Thus, our study may provide a promising candidate for developing the treatment of KSHV-positive diseases and primary effusion lymphoma. Primary effusion lymphoma (PEL), a rare aggressive B-cell lymphoma in immunosuppressed patients, is etiologically associated with oncogenic gamma-herpesvirus infection. Chemotherapy is commonly used to treat PEL but usually results in poor prognosis and survival; thus, novel therapies and drug development are urgently needed for PEL treatment. Here, we demonstrated that inhibition of Ring finger protein 5 (RNF5), an ER-localized E3 ligase, suppresses multiple cellular pathways and lytic replication of Kaposi sarcoma-associated herpesvirus (KSHV) in PEL cells. RNF5 interacts with and induces Ephrin receptors A3 (EphA3) and EphA4 ubiquitination and degradation. RNF5 inhibition increases the levels of EphA3 and EphA4, thereby reducing ERK and Akt activation and KSHV lytic replication. RNF5 inhibition decreased PEL xenograft tumor growth and downregulated viral gene expression, cell cycle gene expression, and hedgehog signaling in xenograft tumors. Our study suggests that RNF5 plays the critical roles in KSHV lytic infection and tumorigenesis of primary effusion lymphoma.