芳香烃受体促进人巨细胞病毒介导的细胞周期 G1/S 阻滞。
The aryl hydrocarbon receptor facilitates the human cytomegalovirus-mediated G1/S block to cell cycle progression.
机构信息
Department of Molecular Biology, Princeton University, Princeton, NJ 08544-1014.
Department of Molecular Biology, Princeton University, Princeton, NJ 08544-1014
出版信息
Proc Natl Acad Sci U S A. 2021 Mar 23;118(12). doi: 10.1073/pnas.2026336118.
The tryptophan metabolite, kynurenine, is known to be produced at elevated levels within human cytomegalovirus (HCMV)-infected fibroblasts. Kynurenine is an endogenous aryl hydrocarbon receptor (AhR) ligand. Here we show that the AhR is activated following HCMV infection, and pharmacological inhibition of AhR or knockdown of AhR RNA reduced the accumulation of viral RNAs and infectious progeny. RNA-seq analysis of infected cells following AhR knockdown showed that the receptor alters the levels of numerous RNAs, including RNAs related to cell cycle progression. AhR knockdown alleviated the G1/S cell cycle block that is normally instituted in HCMV-infected fibroblasts, consistent with its known ability to regulate cell cycle progression and cell proliferation. In sum, AhR is activated by kynurenine and perhaps other ligands produced during HCMV infection, it profoundly alters the infected-cell transcriptome, and one outcome of its activity is a block to cell cycle progression, providing mechanistic insight to a long-known element of the virus-host cell interaction.
色氨酸代谢产物犬尿氨酸在人巨细胞病毒（HCMV）感染的成纤维细胞中已知高水平产生。犬尿氨酸是一种内源性芳烃受体（AhR）配体。在这里，我们表明 AhR 在 HCMV 感染后被激活，AhR 的药理学抑制或 AhR RNA 的敲低减少了病毒 RNA 和感染性后代的积累。AhR 敲低后感染细胞的 RNA-seq 分析表明，该受体改变了许多 RNA 的水平，包括与细胞周期进展相关的 RNA。AhR 敲低缓解了 HCMV 感染的成纤维细胞中通常出现的 G1/S 细胞周期阻滞，这与它已知的调节细胞周期进展和细胞增殖的能力一致。总之，AhR 被犬尿氨酸和 HCMV 感染期间产生的其他配体激活，它深刻地改变了受感染细胞的转录组，其活性的一个结果是阻止细胞周期进程，为病毒-宿主细胞相互作用的一个长期已知元素提供了机制见解。
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