PDF(Pubmed)
Abstract：
Repression of human cytomegalovirus (HCMV) immediate-early (IE) gene expression is a key regulatory step in the establishment and maintenance of latent reservoirs. Viral IE transcription and protein accumulation can be elevated during latency by treatment with histone deacetylase inhibitors such as valproic acid (VPA), rendering infected cells visible to adaptive immune responses. However, the latency-associated viral protein UL138 inhibits the ability of VPA to enhance IE gene expression during infection of incompletely differentiated myeloid cells that support latency. UL138 also limits the accumulation of IFNβ transcripts by inhibiting the cGAS-STING-TBK1 DNA-sensing pathway. Here, we show that, in the absence of UL138, the cGAS-STING-TBK1 pathway promotes both IFNβ accumulation and VPA-responsive IE gene expression in incompletely differentiated myeloid cells. Inactivation of this pathway by either genetic or pharmacological inhibition phenocopied UL138 expression and reduced VPA-responsive IE transcript and protein accumulation. This work reveals a link between cytoplasmic pathogen sensing and epigenetic control of viral lytic phase transcription and suggests that manipulation of pattern recognition receptor signaling pathways could aid in the refinement of MIEP regulatory strategies to target latent viral reservoirs.
摘要：
抑制人巨细胞病毒（HCMV）立即早期（IE）基因表达是建立和维持潜伏储库的关键调控步骤。通过用组蛋白去乙酰化酶抑制剂如丙戊酸（VPA）治疗，病毒IE转录和蛋白质积累可以在潜伏期提高，使感染的细胞对适应性免疫反应可见。然而,潜伏期相关病毒蛋白UL138在支持潜伏期的不完全分化骨髓细胞感染期间抑制VPA增强IE基因表达的能力.UL138还通过抑制cGAS-STING-TBK1DNA传感途径来限制IFNβ转录物的积累。这里,我们证明，在不存在UL138的情况下,cGAS-STING-TBK1途径在不完全分化的骨髓细胞中促进IFNβ积累和VPA反应性IE基因表达。通过遗传或药理抑制使这一途径失活,表现出UL138表达并减少VPA反应性IE转录物和蛋白质积累。这项工作揭示了细胞质病原体传感和病毒裂解期转录的表观遗传控制之间的联系，并表明模式识别受体信号通路的操纵可以帮助MIEP调节策略的细化，以靶向潜伏的病毒储库。
