Chen Qingyang, Li Xiaojuan, Quan Li, Zhou Rihong, Liu Xiangpeng, Cheng Lu, Sarid Ronit, Kuang Ersheng
Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China.
College of Clinical Medicine, Hubei University of Chinese Medicine, Wuhan, Hubei, China.
J Virol. 2024 Dec 17;98(12):e0077924. doi: 10.1128/jvi.00779-24. Epub 2024 Nov 4.
Lytic replication is essential for persistent infection of Kaposi's sarcoma-associated herpesvirus (KSHV) and the pathogenesis of related diseases, and many cellular pathways are hijacked by KSHV proteins to initiate and control the lytic replication of this virus. However, the mechanism involved in KSHV lytic replication from the early to the late phases remains largely undetermined. We previously revealed that KSHV open reading frame 45 (ORF45) plays important roles in late transcription and translation. In the present study, we revealed that the Forkhead box proteins FoxK1 and FoxK2 are ORF45-binding proteins and are essential for KSHV lytic gene expression and virion production, and that depletion of FoxK1 or FoxK2 significantly suppresses the expression of many late viral genes. FoxK1 and FoxK2 directly bind to the promoters of several late viral genes, ORF45 augments the promoter binding and transcriptional activity of FoxK1 and FoxK2, and then FoxK1 or FoxK2 cooperates with ORF45 to promote late viral gene expression. Our findings suggest that ORF45 interacts with FoxK1 and FoxK2 and promotes their occupancy on a cluster of late viral promoters and their subsequent transcriptional activity; consequently, FoxK1 and FoxK2 promote late viral gene expression to facilitate KSHV lytic replication.IMPORTANCEThe forkhead box proteins FoxK1 and FoxK2 can act as transcriptional inhibitors or activators to regulate several important processes, including aerobic glycolysis, metabolism, autophagy, and antiviral responses. However, the subversion and functions of FoxK1 and FoxK2 during KSHV infection and the pathogenesis of related diseases remain unknown. Here, we revealed that ORF45 binds to FoxK1 and FoxK2 and increases their transcriptional activity during KSHV lytic replication; consequently, FoxK1 and FoxK2 bind to late viral promoters and cooperate with ORF45 to promote late lytic gene expression. Our findings reveal two new ORF45 partners and a new function of ORF45 in which it utilizes FoxK1 and FoxK2 to promote transcription during late KSHV lytic replication.
裂解复制对于卡波西肉瘤相关疱疹病毒（KSHV）的持续感染及相关疾病的发病机制至关重要，KSHV蛋白会劫持许多细胞通路来启动和控制该病毒的裂解复制。然而，KSHV从早期到晚期裂解复制所涉及的机制在很大程度上仍未明确。我们之前揭示了KSHV开放阅读框45（ORF45）在晚期转录和翻译中发挥重要作用。在本研究中，我们发现叉头框蛋白FoxK1和FoxK2是ORF45结合蛋白，对KSHV裂解基因表达和病毒粒子产生至关重要，并且敲低FoxK1或FoxK2会显著抑制许多晚期病毒基因的表达。FoxK1和FoxK2直接结合到几个晚期病毒基因的启动子上，ORF45增强FoxK1和FoxK2与启动子的结合及转录活性，然后FoxK1或FoxK2与ORF45协同促进晚期病毒基因表达。我们的研究结果表明，ORF45与FoxK1和FoxK2相互作用，促进它们在一组晚期病毒启动子上的占据及其后续转录活性；因此，FoxK1和FoxK2促进晚期病毒基因表达以利于KSHV裂解复制。
重要性
叉头框蛋白FoxK1和FoxK2可作为转录抑制剂或激活剂来调节包括有氧糖酵解、代谢、自噬和抗病毒反应在内的几个重要过程。然而，FoxK1和FoxK2在KSHV感染及相关疾病发病机制中的颠覆作用和功能仍不清楚。在此，我们揭示了ORF45在KSHV裂解复制过程中与FoxK
