PO.MCB09.05 · 分子与细胞生物学
半胱氨酸氧化是肺癌脑转移所必需的
Cysteine oxidation is required for brain metastasis in lung cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
人们普遍认为大多数半胱氨酸残基需要处于还原状态才具有活性，而其被活性氧（ROS）氧化传统上被视为对蛋白质有害。然而，事实是有些半胱氨酸必须被氧化才能发挥蛋白质功能，但其身份在很大程度上仍属未知。为回答这一问题，我们在55种肺癌细胞系中降低了ROS水平，并采用聚焦半胱氨酸的化学蛋白质组学结合功能性CRISPR筛选来分析其细胞学后果。这一整合方法揭示了数百个受影响、且为增殖所必需的半胱氨酸。我们聚焦于线粒体复合体I中的NDUFA10·C253，发现其在某些人类脑转移灶中处于更氧化的状态。该半胱氨酸受抗氧化通路的动态调控，其氧化是复合体I稳定性所必需的，并支持向脑部的转移。总体而言，我们界定了对细胞适应性及包括转移在内的疾病状态至关重要的氧化型半胱氨酸。
查看英文原文 English abstract
Most cysteine residues are believed to require a reduced state for activity and their oxidation by reactive oxygen species (ROS) is traditionally viewed as damaging to proteins. However, it stands that some cysteines that must be oxidized for protein function, yet their identity remains largely unknown. To answer this question, we lowered ROS levels in 55 lung cancer cell lines and analyzed the cellular consequences using cysteine-focused chemical proteomics paired with functional CRISPR screens. This integrated approach revealed hundreds of impacted cysteines required for proliferation. We focused on NDUFA10•C253 in mitochondrial complex I, which we find exists in a more oxidized state in some human brain metastases. This cysteine is dynamically regulated by antioxidant pathways and its oxidation is required for complex I stability and supports metastasis to the brain. Collectively, we demarcate oxidized cysteines essential for cell fitness and disease states including metastasis.
利益披露 Disclosure
M. Ge, None.