Major-Styles Christine T, Munns Jack, Zeng Aiwei, Vanden Oever Michael, O'Neill John S, Edgar Rachel S
Department of Infectious Disease, Imperial College London, London SW7 2AZ, UK.
Francis Crick Institute, London NW1 1AT, UK.
Philos Trans R Soc Lond B Biol Sci. 2025 Jan 23;380(1918):20230344. doi: 10.1098/rstb.2023.0344.
The within-host environment changes over circadian time and influences the replication and severity of viruses. Genetic knockout of the circadian transcription factors CRYPTOCHROME 1 and CRYPTOCHROME 2 (/; CKO) leads to altered protein homeostasis and chronic activation of the integrated stress response (ISR). The adaptive ISR signalling pathways help restore cellular homeostasis by downregulating protein synthesis in response to endoplasmic reticulum overloading or viral infections. By quantitative mass spectrometry analysis, we reveal that many viral recognition proteins and type I interferon (IFN) effectors are significantly upregulated in lung fibroblast cells from CKO mice compared with wild-type (WT) mice. This basal 'antiviral state' restricts the growth of influenza A virus and is governed by the interaction between proteotoxic stress response pathways and constitutive type I IFN signalling. CKO proteome composition and type I IFN signature were partially phenocopied upon sustained depletion of CRYPTOCHROME (CRY) proteins using a small-molecule CRY degrader, with modest differential gene expression consistent with differences seen between CKO and WT cells. Our results highlight the crosstalk between circadian rhythms, cell-intrinsic antiviral defences and protein homeostasis, providing a tractable molecular model to investigate the interface of these key contributors to human health and disease.This article is part of the Theo Murphy meeting issue 'Circadian rhythms in infection and immunity'.
宿主体内环境会随昼夜节律发生变化，并影响病毒的复制及严重程度。昼夜节律转录因子隐花色素1（CRY1）和隐花色素2（CRY2）基因敲除（/；CKO）会导致蛋白质稳态改变以及整合应激反应（ISR）的慢性激活。适应性ISR信号通路通过在应对内质网过载或病毒感染时下调蛋白质合成，帮助恢复细胞内稳态。通过定量质谱分析，我们发现与野生型（WT）小鼠相比，CKO小鼠肺成纤维细胞中许多病毒识别蛋白和I型干扰素（IFN）效应器显著上调。这种基础的“抗病毒状态”限制了甲型流感病毒的生长，且受蛋白毒性应激反应途径与组成性I型IFN信号传导之间的相互作用调控。使用小分子CRY降解剂持续消耗CRY蛋白后，CKO蛋白质组组成和I型IFN特征部分得到模拟，基因表达差异适度，与CKO和WT细胞之间的差异一致。我们的研究结果突出了昼夜节律、细胞内在抗病毒防御和蛋白质稳态之间的相互作用，为研究这些对人类健康和疾病的关键因素的界面提供了一个易于处理的分子模型。本文是西奥·墨菲会议议题“感染与免疫中的昼夜节律”的一部分。
