Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
College of Clinical Medicine, Hubei University of Chinese Medicine, Wuhan, China.
PLoS Pathog. 2023 Jan 19;19(1):e1011103. doi: 10.1371/journal.ppat.1011103. eCollection 2023 Jan.
Primary effusion lymphoma (PEL), a rare aggressive B-cell lymphoma in immunosuppressed patients, is etiologically associated with oncogenic γ-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.
原发性渗出性淋巴瘤（PEL）是一种罕见的侵袭性 B 细胞淋巴瘤，发生于免疫抑制患者，其病因与致瘤性 γ-疱疹病毒感染有关。化疗通常用于治疗 PEL，但通常预后和生存率较差；因此，迫切需要新的治疗方法和药物开发来治疗 PEL。在这里，我们证明了细胞内定位的 E3 连接酶环指蛋白 5（RNF5）的抑制可抑制 PEL 细胞中卡波济肉瘤相关疱疹病毒（KSHV）的多种细胞途径和裂解复制。RNF5 与 Ephrin 受体 A3（EphA3）和 EphA4 相互作用，并诱导其泛素化和降解。RNF5 的抑制增加了 EphA3 和 EphA4 的水平，从而减少了 ERK 和 Akt 的激活和 KSHV 的裂解复制。RNF5 的抑制降低了 PEL 异种移植肿瘤的生长，并下调了异种移植肿瘤中的病毒基因表达、细胞周期基因表达和 Hedgehog 信号通路。我们的研究表明，RNF5 在 KSHV 的裂解感染和原发性渗出性淋巴瘤的肿瘤发生中起着关键作用。
