Src family kinase activity drives cytomegalovirus reactivation by recruiting MOZ histone acetyltransferase activity to the viral promoter
Src family kinase activity drives cytomegalovirus reactivation by recruiting MOZ histone acetyltransferase activity to the viral promoter
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DOI：
10.1074/jbc.ra119.009667
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发表时间：
2019-08-30
影响因子：
4.8
通讯作者：
Reeves, Matthew B.
中科院分区：
文献类型：
--
作者：
Dupont, Liane;Du, Lily;Reeves, Matthew B.
人巨细胞病毒（HCMV）的潜伏期和再激活依赖于细胞分化、细胞信号传导途径和病毒基因功能之间的复杂相互作用。树突状细胞（DC）中的HCMV再活化是由IL-6和细胞外信号调节激酶（ERK）-促分裂原活化蛋白激酶信号转导触发的。然而，相同途径的激活未能在其他髓样细胞类型中重新激活HCMV，尽管该信号传导轴在这些细胞中是活跃的。我们假设IL-6诱导的ERK激活启动了病毒再激活所需的染色质结构的变化，但是伴随的信号是完成基因表达所需的染色质结构变化所必需的。在支持或不支持IL-6诱导的病毒再活化的细胞中使用差异磷酸化蛋白质组学方法，我们鉴定了Src家族激酶（SFK）、造血细胞激酶（HCK）的伴随活化，特别是在DC中响应IL-6。药理学和遗传学的抑制表明，人巨细胞病毒的再激活所需的人巨细胞蛋白激酶的活性。此外，HCK/SFK活性与单核细胞白血病锌指蛋白（MOZ）组蛋白乙酰转移酶向病毒启动子的募集有关，该启动子在ERK介导的组蛋白磷酸化后促进组蛋白乙酰化。重要的是，MOZ活性的药理学和遗传学抑制阻止了再激活。这些结果为IL-6选择性激活DC中的病毒基因表达提供了解释，依赖于伴随的SFK和ERK信号传导。它们还揭示了SFK活性在真核细胞中通过MOZ组蛋白乙酰转移酶活性调节启动子处的染色质结构中的先前未报道的作用。
Human cytomegalovirus (HCMV) latency and reactivation rely on a complex interplay between cellular differentiation, cell signaling pathways, and viral gene functions. HCMV reactivation in dendritic cells (DCs) is triggered by IL-6 and extracellular signal-regulated kinase (ERK)-mitogen-activated protein kinase signaling. However, activation of the same pathway fails to reactivate HCMV in other myeloid cell types, despite this signaling axis being active in those cells. We hypothesized that IL-6-induced ERK activation initiates the changes in chromatin structure required for viral reactivation but that a concomitant signal is necessary to complete the changes in chromatin structure required for gene expression to occur. Using a differential phosphoproteomics approach in cells that do or do not support IL-6-induced viral reactivation, we identified the concomitant activation of an Src family kinase (SFK), hematopoietic cell kinase (HCK), specifically in DCs in response to IL-6. Pharmacological and genetic inhibition of HCK activity indicated that HCK is required for HCMV reactivation. Furthermore, the HCK/SFK activity was linked to recruitment of the monocytic leukemia zinc finger protein (MOZ) histone acetyltransferase to the viral promoter, which promoted histone acetylation after ERK-mediated histone phosphorylation. Importantly, pharmacological and genetic inhibition of MOZ activity prevented reactivation. These results provide an explanation for the selective activation of viral gene expression in DCs by IL-6, dependent on concomitant SFK and ERK signaling. They also reveal a previously unreported role for SFK activity in the regulation of chromatin structure at promoters in eukaryotic cells via MOZ histone acetyltransferase activity.