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
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
Nature. 2025 Sep 17. doi: 10.1038/s41586-025-09535-5.
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 taurine. 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 liver, 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.
蛋白质对代谢过程的调节是生物学的基础，但目前仍未完全了解。在这里，我们开发了一种基于质谱（MS）的方法，该方法利用遗传多样性来确定活组织中285种代谢物与11,868种蛋白质之间的功能关系。这种方法概括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，同时确定了3542种以前未描述的关系。在此基础上，我们确定了一种由特征不明确的蛋白质LRRC58调节肝脏半胱氨酸利用和胆固醇处理的机制。我们表明，LRRC58是一种E3泛素连接酶的底物适配器，该酶介导CDO1的蛋白酶体降解，CDO1是半胱氨酸分解代谢分流至牛磺酸的限速酶。半胱氨酸丰度调节LRRC58介导的CDO1降解，LRRC58的缺失足以稳定CDO1，从而驱动半胱氨酸消耗以产生牛磺酸。牛磺酸在胆固醇处理中起核心作用，促进其从肝脏排泄，并且我们表明肝细胞中LRRC58的缺失会增加半胱氨酸向牛磺酸的通量，并降低小鼠肝脏中的胆固醇。揭示LRRC58控制半胱氨酸分解代谢的机制例证了协变质谱在识别代谢过程蛋白质调节模式方面的效用。
