Liu Jinmin, Kulkarni Amogh, Gao Yong-Qi, Urul Daniel A, Hamelin Romain, Novotny Balázs Á, Long Marcus J C, Aye Yimon
Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK; Swiss Federal Institute of Technology Lausanne, Lausanne 1015, Switzerland.
Swiss Federal Institute of Technology Lausanne, Lausanne 1015, Switzerland; Friedrich Schiller University, 07737 Jena, Germany.
Cell. 2024 Dec 26;187(26):7450-7469.e29. doi: 10.1016/j.cell.2024.10.014. Epub 2024 Nov 5.
Proximity labeling technologies are limited to indexing localized protein residents. Such data-although valuable-cannot inform on small-molecule responsivity of local residents. We here bridge this gap by demonstrating in live C. elegans how electrophile-sensing propensity in specific organs can be quantitatively mapped and ranked. Using this method, >70% of tissue-specific responders exhibit electrophile responsivity, independent of tissue-specific abundance. One responder, cyp-33e1-for which both human and worm orthologs are electrophile responsive-marshals stress-dependent gut functions, despite manifesting uniform abundance across all tissues studied. Cyp-33e1's localized electrophile responsivity operates site specifically, triggering multifaceted responses: electrophile sensing through the catalytic-site cysteine results in partitioning between enzyme inhibition and localized production of a critical metabolite that governs global lipid availability, whereas rapid dual-cysteine site-specific sensing modulates gut homeostasis. Beyond pinpointing chemical actionability within local proteomes, organ-specific electrophile responsivity mapping illuminates otherwise intractable locale-specific metabolite signaling and stress response programs influencing organ-specific decision-making.
邻近标记技术仅限于对局部蛋白质驻留物进行索引。这些数据虽然有价值，但无法提供有关局部驻留物小分子反应性的信息。我们在此通过在活的秀丽隐杆线虫中展示如何对特定器官中的亲电体感应倾向进行定量映射和排序来弥合这一差距。使用这种方法，超过70%的组织特异性反应者表现出亲电体反应性，与组织特异性丰度无关。一个反应者cyp-33e1（其人类和线虫直系同源物均对亲电体有反应），尽管在所有研究的组织中表现出均匀的丰度，但它协调依赖应激的肠道功能。Cyp-33e1的局部亲电体反应性在特定位点起作用，引发多方面的反应：通过催化位点半胱氨酸进行亲电体感应导致在酶抑制和控制全局脂质可用性的关键代谢物的局部产生之间进行分配，而快速的双半胱氨酸位点特异性感应调节肠道稳态。除了确定局部蛋白质组内的化学可作用性外，器官特异性亲电体反应性映射还揭示了影响器官特异性决策的原本难以处理的局部特异性代谢物信号传导和应激反应程序。
