Covariation MS uncovers a protein that controls cysteine catabolism A new study led by the Chouchani Lab at Harvard Medical School has identified a previously unknown regulatory mechanism in cellular metabolism, revealing that a protein called LRRC58 controls the catabolism of cysteine into taurine. This discovery was made using a novel machine learning approach called Metabolite–Protein Covariation Architecture (MPCA), which analyzes abundance patterns of proteins and metabolites across genetically diverse living tissues. The research team used a cohort of 163 female Diversity Outbred (DO) mice—genetically heterogeneous animals that mirror human genetic diversity—to profile 11,868 proteins and 285 metabolites in liver and brown adipose tissue. By measuring how the abundance of these molecules co-varied across individuals, the researchers built MPCA, a comprehensive map of potential functional relationships between metabolites and proteins. Using LASSO regression—a statistical method that identifies the most predictive proteins for metabolite levels—MPCA flagged 3,542 previously uncharacterized protein–metabolite interactions. The method successfully recapitulated known biochemical reactions and identified novel regulators, including LRRC58, a protein with no previously known metabolic role. The team focused on cysteine catabolism, a critical pathway that converts cysteine into hypotaurine and taurine. This process is essential for regulating cellular cysteine levels, influencing glutathione production, iron metabolism, and preventing cysteine toxicity. The rate-limiting enzyme in this pathway, CDO1, is tightly regulated post-transcriptionally, but the mechanism was unclear. MPCA analysis revealed that LRRC58 was the strongest negative predictor of hypotaurine abundance. Functional validation in human liver cells (HepG2) and primary mouse hepatocytes confirmed that knocking down LRRC58 increased hypotaurine and taurine levels by up to fivefold, while overexpressing LRRC58 reduced them. This effect was mediated through CDO1: LRRC58 depletion stabilized CDO1 protein levels, whereas LRRC58 overexpression reduced them. Further investigation showed that LRRC58 acts as a substrate adaptor for a Cullin-5 RING E3 ubiquitin ligase (CRL5) complex. This complex targets CDO1 for ubiquitylation and degradation by the proteasome. Structural modeling using AlphaFold2 predicted a direct interaction between LRRC58 and CDO1, and biochemical assays confirmed this binding and the dependence of CDO1 degradation on LRRC58. Importantly, the system responds to cellular cysteine levels: when cysteine is abundant, CDO1 is stabilized; when cysteine is low, LRRC58 promotes CDO1 degradation. This feedback loop ensures cysteine is preserved for essential functions like glutathione synthesis when levels are low, while allowing its catabolism into taurine when surplus. In vivo experiments in mice showed that liver-specific knockdown of LRRC58 led to an 18-fold increase in CDO1, a 24.7% reduction in hepatic cholesterol, and a 35.6% drop in hepatic cysteine. These changes were linked to increased flux of cysteine into taurine and enhanced bile acid excretion, suggesting a key role for LRRC58 in cholesterol homeostasis. The study demonstrates that LRRC58 functions as a metabolic sensor that fine-tunes cysteine metabolism based on availability. This regulatory axis could be a therapeutic target for diseases involving cholesterol imbalance, fatty liver disease, or oxidative stress. The MPCA resource, available at https://mpca-chouchani-lab.dfci.harvard.edu/, provides a powerful tool for discovering new protein–metabolite relationships across tissues and species, advancing our understanding of metabolic regulation in health and disease.