加州大学Michael Rap研究团队取得一项新突破。他们报道了综合应激反应中SIFI活性的分子基础。该项研究成果发表在2025年5月6日出版的《自然》上。

该团队将内源性SIFI冷冻电镜与AlphaFold建模和生化分析相结合，报告了综合应激反应沉默的结构和机制基础。SIFI通过易于接近的支架内的柔性结构域检测应力指标和应力响应成分，然后在单独的、空间受限的延伸模块上构建链接特异性泛素链。泛素传递通过泛素样结构域偶联通用底物修饰到连接特异性泛素聚合物的形成。因此，应激反应沉默利用了一种催化机制，该机制旨在处理多种不同的蛋白质，从而允许一种酶监测并在需要时调节复杂的细胞状态。

研究人员表示，慢性应激反应激活损害细胞存活并诱发破坏性退行性疾病。生物体相应地部署沉默因子，如E3泛素连接酶SIFI，以终止应激反应信号传导并确保细胞内稳态。沉默因子如何在细胞尺度上感知压力，从而引发及时的应激反应失活，目前尚不清楚。

附：英文原文

Title: Molecular basis of SIFI activity in the integrated stress response

Author: Yang, Zhi, Haakonsen, Diane L., Heider, Michael, Witus, Samuel R., Zelter, Alex, Beschauner, Tobias, MacCoss, Michael J., Rap, Michael

Issue&Volume: 2025-05-06

Abstract: Chronic stress response activation impairs cell survival and causes devastating degenerative di-seases 1-3. Organisms accordingly deploy silencing factors, such as the E3 ubiquitin ligase SIFI, to terminate stress response signaling and ensure cellular homeostasis 4. How a silencing factor can sense stress across cellular scales to elicit timely stress response inactivation is poorly understood. Here, we combine cryo-electron microscopy of endogenous SIFI with AlphaFold modeling and biochemical analyses to report the structural and mechanistic basis of integrated stress response silencing. SIFI detects both stress-indicators and stress response components through flexible domains within an easily accessible scaffold, before building linkage-specific ubiquitin chains at separate, sterically restricted elongation modules. Ubiquitin handover by a ubiquitin-like domain couples versatile substrate modification to linkage-specific ubiquitin polymer formation. Stress response silencing therefore exploits a catalytic mechanism that is geared towards processing many diverse proteins and hence allows a single enzyme to monitor and, if needed, modulate a complex cellular state.

DOI: 10.1038/s41586-025-09074-z

Source: https://www.nature.com/articles/s41586-025-09074-z