Sandhu Praneet Kaur, Damania Blossom
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
PLoS Pathog. 2025 Apr 21;21(4):e1013009. doi: 10.1371/journal.ppat.1013009. eCollection 2025 Apr.
Human gammaherpesviruses comprise of Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV), and are oncogenic viruses that cause life-long infections. The gammaherpesviruses utilize an extensive virus-host interaction network for facilitating viral replication, whereby virus-encoded proteins modulate host processes. Thus, identifying targets of viral proteins that aid in gammaherpesviral replication will help develop therapies to combat these viruses. We identified that host proteins DDX5 and DDX17 interact with gammaherpesviral protein kinases, KSHV-encoded vPK and EBV-encoded BGLF4. We found that DDX5 and DDX17 are required for gammaherpesviral lytic reactivation and loss of both DDX5 and DDX17 decreased KSHV and EBV lytic reactivation. Depletion of DDX5 and DDX17 lowered the transcription of KSHV RTA, the key viral gene that drives the lytic replication cascade, due to reduced occupancy of Brg1, a chromatin remodeler, at the RTA promoter. Consequently, inhibition of Brg1 decreased gammaherpesviral lytic reactivation. Here we demonstrate how gammaherpesviruses hijack the function of two host proteins to promote their lytic replication cycle.
人类γ-疱疹病毒包括卡波西肉瘤相关疱疹病毒（KSHV）和爱泼斯坦-巴尔病毒（EBV），是可导致终身感染的致癌病毒。γ-疱疹病毒利用广泛的病毒-宿主相互作用网络来促进病毒复制，在此过程中病毒编码的蛋白质会调节宿主进程。因此，鉴定有助于γ-疱疹病毒复制的病毒蛋白靶点将有助于开发对抗这些病毒的疗法。我们发现宿主蛋白DDX5和DDX17与γ-疱疹病毒蛋白激酶相互作用，即KSHV编码的vPK和EBV编码的BGLF4。我们发现DDX5和DDX17是γ-疱疹病毒裂解再激活所必需的，同时缺失DDX5和DDX17会降低KSHV和EBV的裂解再激活。由于染色质重塑因子Brg1在RTA启动子处的占有率降低，DDX5和DDX17的缺失降低了KSHV RTA的转录，KSHV RTA是驱动裂解复制级联反应的关键病毒基因。因此，抑制Brg1会降低γ-疱疹病毒的裂解再激活。在此我们展示了γ-疱疹病毒如何劫持两种宿主蛋白的功能来促进其裂解复制周期。
