Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
Cell. 2020 Mar 5;180(5):968-983.e24. doi: 10.1016/j.cell.2020.02.012. Epub 2020 Feb 27.
Mammalian tissues engage in specialized physiology that is regulated through reversible modification of protein cysteine residues by reactive oxygen species (ROS). ROS regulate a myriad of biological processes, but the protein targets of ROS modification that drive tissue-specific physiology in vivo are largely unknown. Here, we develop Oximouse, a comprehensive and quantitative mapping of the mouse cysteine redox proteome in vivo. We use Oximouse to establish several paradigms of physiological redox signaling. We define and validate cysteine redox networks within each tissue that are tissue selective and underlie tissue-specific biology. We describe a common mechanism for encoding cysteine redox sensitivity by electrostatic gating. Moreover, we comprehensively identify redox-modified disease networks that remodel in aged mice, establishing a systemic molecular basis for the long-standing proposed links between redox dysregulation and tissue aging. We provide the Oximouse compendium as a framework for understanding mechanisms of redox regulation in physiology and aging.
哺乳动物组织具有专门的生理学功能，这些功能通过活性氧（ROS）可逆修饰蛋白质半胱氨酸残基来调节。ROS 调节着无数的生物过程，但驱动体内组织特异性生理学的 ROS 修饰的蛋白质靶标在很大程度上是未知的。在这里，我们开发了 Oximouse，这是一种在体内全面定量映射小鼠半胱氨酸氧化还原蛋白质组的方法。我们使用 Oximouse 来建立几种生理氧化还原信号传递的范例。我们定义并验证了每个组织内的半胱氨酸氧化还原网络，这些网络具有组织选择性，是组织特异性生物学的基础。我们描述了一种通过静电门控来编码半胱氨酸氧化还原敏感性的常见机制。此外，我们还全面鉴定了在老年小鼠中重塑的氧化还原修饰疾病网络，为氧化还原失调与组织衰老之间长期存在的关联提供了系统的分子基础。我们提供了 Oximouse 纲要，作为理解生理和衰老过程中氧化还原调节机制的框架。
