Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
Centennial High School, Ellicott City, Maryland, United States of America.
PLoS Pathog. 2018 May 10;14(5):e1007058. doi: 10.1371/journal.ppat.1007058. eCollection 2018 May.
Human herpesvirus 8 (HHV-8) is causally related to human malignancies. HHV-8 latent viral FLICE-inhibitory protein (vFLIP) is a viral oncoprotein that is linked to pathogenesis, but how its expression is regulated is largely unknown. In an attempt to understand the role of the mitochondrial antiviral signaling (MAVS) adaptor in HHV-8 infection, we discovered that vFLIP expression was post-translationally up-regulated by the MAVS signaling complex on peroxisomes. Furthermore, we demonstrated that vFLIP could be targeted to the peroxisomes, where it was oncogenically active, in a PEX19-dependent manner. Targeted disruption of vFLIP and MAVS interaction resulted in a decrease in vFLIP expression and selectively promoted death of latently HHV-8-infected cells, providing therapeutic potential for treating HHV-8 diseases. Collectively, our experimental results suggest novel involvement of peroxisomes and MAVS in the stabilization of vFLIP and thereby in the establishment or maintenance of HHV-8 latency and associated pathogenesis.
人类疱疹病毒 8 型（HHV-8）与人类恶性肿瘤有因果关系。HHV-8 潜伏性病毒 FLICE 抑制蛋白（vFLIP）是一种病毒癌蛋白，与发病机制有关，但它的表达如何调节在很大程度上尚不清楚。为了了解线粒体抗病毒信号（MAVS）衔接蛋白在 HHV-8 感染中的作用，我们发现 vFLIP 的表达在后翻译水平上被过氧化物酶体上的 MAVS 信号复合物上调。此外，我们证明 vFLIP 可以通过 PEX19 依赖性方式靶向过氧化物酶体，在那里它具有致癌活性。靶向破坏 vFLIP 和 MAVS 的相互作用导致 vFLIP 表达减少，并选择性促进潜伏性 HHV-8 感染细胞的死亡，为治疗 HHV-8 疾病提供了治疗潜力。总的来说，我们的实验结果表明过氧化物酶体和 MAVS 参与 vFLIP 的稳定，从而参与 HHV-8 潜伏和相关发病机制的建立或维持。
