Epstein-Barr virus protein BKRF4 restricts nucleosome assembly to suppress host antiviral responses.
Epstein-Barr virus protein BKRF4 restricts nucleosome assembly to suppress host antiviral responses.
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DOI：
10.1073/pnas.2203782119
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发表时间：
2022-09-13
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
核小体束缚是病毒减弱宿主DNA损伤反应（DDR）信号和协调病毒生命周期的常见机制。EB病毒被膜蛋白BKRF 4通过组蛋白伴侣样序列与组蛋白H2 A-H2 B相互作用。“三锚”结合模式和DWP基序赋予BKRF 4比许多其他H2 A-H2 B伴侣蛋白更强的H2 A-H2 B结合。引人注目的是，BKRF 4仅在核小体部分分解并在DNA断裂处积累时才结合核小体，其中染色质需要在修复之前分解。我们的研究结果揭示了组蛋白伴侣模拟策略用于病毒抑制宿主DDR信号。抑制宿主DNA损伤反应（DDR）是病毒操纵宿主细胞机制和编排病毒生命周期的常见机制。EB病毒被膜蛋白BKRF 4与细胞染色质结合抑制宿主DDR信号传导，但其潜在机制尚不清楚。在这里，我们确定了一个BKRF 4组蛋白结合域（残基15-102，称为BKRF 4-HBD），可以在DNA损伤位点积累，破坏53 BP 1灶的形成。BKRF 4-HBD与人H2 A-H2 B二聚体复合物的高分辨率结构显示，BKRF 4-HBD通过N-末端区域（NTR）、DWP基序（残基80-86，包含D81、W84、P86）和C-末端区域（CTR）与H2 A-H2 B二聚体相互作用。“三锚”结合模式赋予BKRF 4-HBD与部分未折叠的核小体缔合的能力，从而促进核小体解体。重要的是，破坏BKRF 4-H2 A-H2 B相互作用在体外损害BKRF 4-HBD与核小体之间的结合，并在体内抑制BKRF 4-HBD募集至DNA断裂。总之，我们的研究揭示了BKRF 4与部分未折叠核小体结合的结构基础，并阐明了宿主DDR信号衰减的非常规机制。
Nucleosome tethering is a common mechanism used by viruses to attenuate host DNA-damage-response (DDR) signals and orchestrate viral life cycles. The Epstein-Barr virus tegument protein BKRF4 interacts with histone H2A–H2B via a histone chaperone-like sequence. The “triple-anchor” binding mode and a DWP motif confers BKRF4 a stronger H2A–H2B binding than many other H2A–H2B chaperones. Strikingly, BKRF4 only binds nucleosomes when they are partially disassembled and accumulates at DNA breaks, where chromatin needs to be disassembled prior to repair. Our findings reveal a histone chaperone mimicry strategy used by viruses to inhibit host DDR signaling. Inhibition of host DNA damage response (DDR) is a common mechanism used by viruses to manipulate host cellular machinery and orchestrate viral life cycles. Epstein-Barr virus tegument protein BKRF4 associates with cellular chromatin to suppress host DDR signaling, but the underlying mechanism remains elusive. Here, we identify a BKRF4 histone binding domain (residues 15–102, termed BKRF4-HBD) that can accumulate at the DNA damage sites to disrupt 53BP1 foci formation. The high-resolution structure of the BKRF4-HBD in complex with a human H2A–H2B dimer shows that BKRF4-HBD interacts with the H2A–H2B dimer via the N-terminal region (NTR), the DWP motif (residues 80–86 containing D81, W84, P86), and the C-terminal region (CTR). The “triple-anchor” binding mode confers BKRF4-HBD the ability to associate with the partially unfolded nucleosomes, promoting the nucleosome disassembly. Importantly, disrupting the BKRF4–H2A–H2B interaction impairs the binding between BKRF4-HBD and nucleosome in vitro and inhibits the recruitment of BKRF4-HBD to DNA breaks in vivo. Together, our study reveals the structural basis of BKRF4 bindings to the partially unfolded nucleosome and elucidates an unconventional mechanism of host DDR signal attenuation.
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