共变质谱揭示了一种控制半胱氨酸分解代谢的蛋白质，这一成果由丹娜法伯癌症研究所Edward T. Chouchani研究小组经过不懈努力而取得。这一研究成果发表在2025年9月17日出版的国际学术期刊《自然》上。

在这里，课题组研究人员开发了一种基于质谱（MS）的方法，利用遗传多样性来确定活组织中285种代谢物和11868种蛋白质之间的功能关系。该方法概述了由直接物理相互作用和局部代谢途径调节介导的蛋白质-代谢物功能关系，同时提名了3542种先前未描述的关系。在此基础上，该课题组人员确定了肝脏半胱氨酸利用和胆固醇处理的调节机制，该机制由特征不明确的蛋白LRRC58调节。

该课题组发现LRRC58是E3泛素连接酶的底物适配器，介导CDO1的蛋白酶体降解，CDO1是半胱氨酸到牛磺酸的分解代谢分流的限速酶。半胱氨酸丰度调节LRRC58介导的CDO1降解，LRRC58的消耗足以稳定CDO1，从而驱动半胱氨酸消耗产生牛磺酸。牛磺酸在胆固醇处理中发挥核心作用，促进其从肝脏排出，小组发现肝细胞中LRRC58的消耗增加了半胱氨酸流向牛磺酸并降低了小鼠的肝脏胆固醇。揭示LRRC58控制半胱氨酸分解代谢的机制，体现了共变质谱在识别蛋白质调节代谢过程模式方面的实用性。

研究人员表示，蛋白质对代谢过程的调节是生物学的基础，但尚未完全了解。

附：英文原文

Title: Covariation MS uncovers a protein that controls cysteine catabolism

Author: Xiao, Haopeng, Ordonez, Martha, Fink, Emma C., Covington, Taylor A., Woldemichael, Hilina B., Chen, Junyi, Jain, Mika Sarkin, Rohatgi, Milan H., Wei, Shelley M., Burger, Nils, Sharif, Muneeb A., Jan, Julius, Wang, Yaoyu, Petrocelli, Jonathan J., Blackmore, Katherine, Smythers, Amanda L., Zhang, Bingsen, Gilbert, Matthew, Cheong, Hakyung, Khetarpal, Sumeet A., Smith, Arianne, Bogoslavski, Dina, Lei, Yu, Vaites, Laura Pontano, McAllister, Fiona E., Van Bruggen, Nick, Donovan, Katherine A., Huttlin, Edward L., Mills, Evanna L., Fischer, Eric S., Chouchani, Edward T.

Issue&Volume: 2025-09-17

Abstract: The regulation of metabolic processes by proteins is fundamental to biology and yet is incompletely understood. Here we develop a mass spectrometry (MS)-based approach that leverages genetic diversity to nominate functional relationships between 285 metabolites and 11,868 proteins in living tissues. This method recapitulates protein–metabolite functional relationships mediated by direct physical interactions and local metabolic pathway regulation while nominating 3,542 previously undescribed relationships. With this foundation, we identify a mechanism of regulation over liver cysteine utilization and cholesterol handling, regulated by the poorly characterized protein LRRC58. We show that LRRC58 is the substrate adaptor of an E3 ubiquitin ligase that mediates proteasomal degradation of CDO1, the rate-limiting enzyme of the catabolic shunt of cysteine to taurine1. Cysteine abundance regulates LRRC58-mediated CDO1 degradation, and depletion of LRRC58 is sufficient to stabilize CDO1 to drive consumption of cysteine to produce taurine. Taurine has a central role in cholesterol handling, promoting its excretion from the liver2, and we show that depletion of LRRC58 in hepatocytes increases cysteine flux to taurine and lowers hepatic cholesterol in mice. Uncovering the mechanism of LRRC58 control over cysteine catabolism exemplifies the utility of covariation MS to identify modes of protein regulation of metabolic processes.

DOI: 10.1038/s41586-025-09535-5

Source: https://www.nature.com/articles/s41586-025-09535-5