PSL大学Nicolas Manel小组的一项最新研究揭示了由病毒蛋白触发的着丝粒DNA扩增激活核cGAS。相关论文于2025年6月2日发表在《细胞》杂志上。

课题组人员发现几种疱疹病毒蛋白通过扰乱富含cGAS的着丝粒来触发核cGAS激活。单纯疱疹病毒1型（HSV-1）泛素连接酶感染细胞蛋白0 (ICP0)，降解着丝粒蛋白，在静止的单核细胞源性细胞中通过翻译DNA合成（TLS）途径促进着丝粒DNA扩增，从而激活核cGAS。在感染期间，HSV-1也通过表达UL36USP （TLS的抑制因子）来逃避这种检测。与ICP0类似，巨细胞病毒IE1蛋白也会引起着丝粒DNA扩增和cGAS激活。小组将这一机制定义为病毒诱导的着丝粒DNA扩增和识别（VICAR），揭示了着丝粒的非有丝分裂免疫激活作用。

研究人员表示，cGAS-cGAMP-STING通路对抗病毒免疫至关重要。虽然细胞质cGAS检测病毒DNA，但大多数DNA病毒主题保护其基因组并侵入核，而核染色质限制了cGAS的激活。病毒主题如何激活核cGAS尚不清楚。

附：英文原文

Title: Centromeric DNA amplification triggered by viral proteins activates nuclear cGAS

Author: Xavier Lahaye, Patrick Tran Van, Camellia Chakraborty, Anna Shmakova, Ngoc Tran Bich Cao, Hermine Ferran, Ouardia Ait-Mohamed, Mathieu Maurin, Joshua J. Waterfall, Benedikt B. Kaufer, Patrick Fischer, Thomas Hennig, Lars Dlken, Patrick Lomonte, Daniele Fachinetti, Nicolas Manel

Issue&Volume: 2025-06-02

Abstract: The cGAS-cGAMP-STING pathway is crucial for antiviral immunity. While cytosolic cGAS detects viral DNA, most DNA viruses shield their genome and invade the nucleus, where chromatin restricts cGAS activation. How viruses may activate nuclear cGAS is not well understood. Here, we show that several herpesvirus proteins trigger nuclear cGAS activation by perturbing centromeres, where cGAS is enriched. The herpes simplex virus type 1 (HSV-1) ubiquitin ligase infected cell protein 0 (ICP0), which degrades centromeric proteins, promotes centromeric DNA amplification through the translesion DNA synthesis (TLS) pathway in quiescent monocyte-derived cells, thereby activating nuclear cGAS. During infection, HSV-1 evades this detection by also expressing UL36USP, a suppressor of TLS. Similarly to ICP0, the cytomegalovirus IE1 protein causes centromeric DNA amplification and cGAS activation. We define this mechanism as viral-induced centromeric DNA amplification and recognition (VICAR), uncovering a non-mitotic, immune-activating role of centromeres.

DOI: 10.1016/j.cell.2025.05.008

Source: https://www.cell.com/cell/abstract/S0092-8674(25)00556-2