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Metabolite-protein covariation architecture identifies a cysteine shunt regulating liver cholesterol

ABSTRACT: Protein regulation of metabolic processes is foundational to biology. Here we develop a mass spectrometry-based approach that leverages genetic diversity to nominate functional relationships between 285 metabolites and 11,868 proteins in living tissues. This Metabolite Protein Covariation Architecture (MPCA) recapitulates protein-metabolite functional relationships mediated by direct physical interactions and local metabolic pathway regulation, while nominating 3,542 relationships not previously described. Using MPCA, we discover a mechanism of regulation over liver cysteine utilization and cholesterol handling, regulated by the poorly characterized protein leucine rich repeats-containing protein 58 (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 hypotaurine-taurine pathway1. 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 is central to cholesterol handling by promoting its excretion from the liver2, and we show that depletion of LRRC58 in hepatocytes elevates cysteine flux to taurine, and is sufficient to lower hepatic cholesterol in mice. Uncovering a mechanism of LRRC58 regulation over the cysteine shunt to taurine exemplifies the utility of MPCA as a platform to identify modes of protein regulation of metabolic processes.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Hepatocyte, Liver, Brown Fat Cell

SUBMITTER: Haopeng Xiao

LAB HEAD: Haopeng Xiao

PROVIDER: PXD065355 | Pride | 2025-07-28

REPOSITORIES: Pride

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			Action	DRS
	B6_liver_KD.xlsx	Xlsx
	BAT_cells_KD.xlsx	Xlsx
	DO_liver_proteomics.xlsx	Xlsx
	HEPG2_OE.xlsx	Xlsx
	Hepatocytes_KD.xlsx	Xlsx

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