New Protein LRRC58 Found to Control Cysteine Breakdown and Liver Cholesterol
A novel mass spectrometry method maps 482,000 protein-metabolite relationships, revealing how LRRC58 governs cysteine catabolism and hepatic cholesterol.
Summary
Researchers developed Covariation MS — a technique combining proteomics and metabolomics in 163 genetically diverse mice — to map functional relationships between 11,868 proteins and 285 metabolites. This produced a Metabolite-Protein Covariation Architecture (MPCA) nominating 3,542 previously unknown protein-metabolite relationships. Using MPCA, they identified LRRC58, a poorly characterized protein, as the substrate adaptor of an E3 ubiquitin ligase that targets CDO1 — the rate-limiting enzyme converting cysteine to taurine — for proteasomal degradation. Cysteine abundance itself regulates this process. Depleting LRRC58 in mouse hepatocytes stabilizes CDO1, increases taurine production, and lowers hepatic cholesterol, as taurine promotes bile acid-mediated cholesterol excretion.
Detailed Summary
Understanding how proteins regulate metabolic processes is central to biology, yet most regulatory relationships — especially those not based on direct physical interactions — remain unmapped. Current methods require purified proteins or metabolites and operate outside native cellular environments, missing indirect or pathway-level regulation that is widespread in living systems.
To address this, the authors developed Covariation MS and its analytical framework, MPCA (Metabolite-Protein Covariation Architecture). Using 163 fully genotyped diversity outbred (DO) female mice — whose genetic variability mirrors that of humans — they performed deep quantitative proteomics (11,868 proteins) and metabolomics (285 metabolites) on liver and brown adipose tissue (BAT). The genetic heterogeneity of the DO cohort drove substantial inter-individual variation, enabling derivation of 482,043 statistically significant protein-metabolite correlation pairs at a 5% FDR. MPCA successfully recapitulated known enzyme-metabolite relationships (e.g., succinate and NAD⁺ with electron transport chain proteins) while nominating 3,542 entirely new functional relationships.
Focusing on cysteine catabolism — a metabolically important but poorly understood pathway — MPCA highlighted LRRC58, a leucine-rich repeat-containing protein with no previously defined function. Mechanistic experiments demonstrated that LRRC58 acts as the substrate adaptor for an E3 ubiquitin ligase complex that selectively targets CDO1 (cysteine dioxygenase 1), the rate-limiting enzyme of the cysteine-to-taurine catabolic shunt, for proteasomal degradation. Critically, cellular cysteine abundance itself regulates this system: when cysteine is plentiful, LRRC58-mediated CDO1 degradation is suppressed, allowing greater CDO1 activity and cysteine flux toward taurine. This creates a self-correcting feedback mechanism controlling cysteine levels.
Taurine, the product of CDO1 activity, is a key conjugate for bile acids that facilitates cholesterol excretion from the liver. Knockdown of LRRC58 in mouse hepatocytes stabilized CDO1, increased taurine biosynthesis, enhanced cysteine flux through the catabolic shunt, and significantly lowered hepatic cholesterol. This positions the LRRC58–CDO1 axis as a tractable regulatory node linking amino acid catabolism to cholesterol homeostasis.
The MPCA resource is publicly accessible online, offering the research community a searchable atlas of protein-metabolite functional relationships to guide future mechanistic studies across metabolism, disease biology, and drug target discovery.
Key Findings
- MPCA mapped 482,043 protein-metabolite correlation pairs in living mouse tissues, nominating 3,542 new functional relationships.
- LRRC58 was identified as an E3 ubiquitin ligase adaptor that drives proteasomal degradation of CDO1, the rate-limiting cysteine catabolic enzyme.
- Cellular cysteine abundance regulates LRRC58-mediated CDO1 degradation, forming a feedback loop controlling cysteine utilization.
- LRRC58 depletion in hepatocytes stabilizes CDO1, boosts taurine production, and lowers hepatic cholesterol in mice.
- The covariation MS approach captures indirect, pathway-level protein-metabolite regulation not detectable by existing in vitro methods.
Methodology
The study used 163 genetically diverse diversity outbred female mice, profiling 11,868 proteins and 285 metabolites in liver and BAT by mass spectrometry. Abundance covariation across individuals was analyzed with the MPCA machine learning framework at 5% FDR to nominate functional relationships. Mechanistic follow-up used LRRC58 knockdown in hepatocytes and in vivo mouse models to validate the CDO1 ubiquitination and cholesterol phenotype.
Study Limitations
The study was conducted exclusively in female mice, limiting generalizability to males and humans. Metabolite coverage was restricted to 285 measured species, potentially missing important regulatory relationships. The in vivo hepatocyte depletion model demonstrates association but causality in human liver physiology remains to be established.
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