LRRC58

LRRC58 is a leucine-rich repeat protein that functions as the substrate adaptor of a CUL2/CUL5-based cullin-RING E3 ubiquitin ligase complex, targeting cysteine dioxygenase 1 (CDO1) for proteasomal degradation at Lys8 to maintain cysteine homeostasis (PMID:40963025, PMID:41270722). LRRC58 stability is itself inversely regulated by cysteine availability: cysteine-replete conditions trigger LRRC58 auto-ubiquitination and self-degradation, whereas cysteine deprivation stabilizes LRRC58 to promote CDO1 turnover, thereby preventing ferroptotic cell death caused by futile cysteine catabolism (PMID:40963025). In mice, hepatocyte-specific LRRC58 depletion stabilizes CDO1, redirecting cysteine flux toward taurine and bile acid conjugation and lowering hepatic cholesterol (PMID:40963025). Independently of its protein-coding function, the Lrrc58 3′ UTR serves as a target-directed miRNA degradation (TDMD) trigger RNA that recruits miR-503-5p to AGO for ZSWIM8-dependent destruction, and deletion of this trigger site in mice causes miR-503-dependent embryonic growth restriction (PMID:41213800, PMID:40631113).

1. 2025 Medium

   Establishing that LRRC58 ortholog lrr-2 post-translationally controls CDO1 levels in C. elegans revealed a conserved regulatory axis in sulfur amino acid metabolism, answering the question of how cysteine dioxygenase abundance is tuned across metazoans.

   Evidence Forward genetic selection and epistasis analysis in C. elegans with H₂S rescue experiments

   PMID:39786993

   Open questions at the time

   • Single-lab genetic study in a model organism; biochemical mechanism of regulation not defined
   • Direct physical interaction between lrr-2 and cdo-1 not demonstrated
   • No mammalian validation at that time
2. 2025 High

   Identification of LRRC58 as the substrate adaptor of a CUL2/CUL5 E3 ligase complex that ubiquitylates CDO1 at Lys8, combined with cryo-EM structure and demonstration that cysteine abundance inversely regulates LRRC58 stability via auto-ubiquitination, established the complete molecular logic of a nutrient-sensing degradation switch for cysteine homeostasis.

   Evidence Metabolite-protein covariation mass spectrometry, cryo-EM structural analysis, biochemical reconstitution of CRL complex, saturation mutagenesis stability profiling, active CRL profiling, and in vivo hepatocyte depletion in mice across multiple independent laboratories

   PMID:40963025 PMID:41270722

   Open questions at the time

   • Structural basis for cysteine sensing by LRRC58 (how cysteine triggers auto-ubiquitination) not fully resolved
   • Whether additional substrates beyond CDO1 are targeted by the LRRC58-CRL complex is unknown
   • Tissue-specific regulation outside liver not characterized
3. 2025 Medium

   Demonstrating that LRRC58-mediated CDO1 degradation prevents ferroptosis under cysteine scarcity, and that patient CDO1 mutations causing neurodevelopmental defects escape LRRC58 recognition, linked this ubiquitin ligase axis to human disease and cell survival.

   Evidence Cell death assays under cysteine deprivation, saturation mutagenesis of CDO1-LRRC58 binding interface, analysis of patient-derived CDO1 mutations (preprint)

   PMID:bio_10.1101_2025.09.23.678073

   Open questions at the time

   • Preprint not yet peer-reviewed; disease-causative CDO1 mutations need independent clinical validation
   • Whether LRRC58 loss alone is sufficient for ferroptosis in vivo is untested
   • Mechanism by which dominant-active CDO1 mutants evade LRRC58 recognition not structurally defined
4. 2025 High

   Discovery that the Lrrc58 3′ UTR functions as a TDMD trigger RNA for miR-503-5p, driving ZSWIM8-dependent AGO degradation and miRNA turnover, revealed a second, protein-coding-independent biological function of the LRRC58 locus in controlling embryonic body growth.

   Evidence AGO-CLASH, CRISPR deletion of the trigger site in the mouse Lrrc58 3′ UTR, body size phenotyping, miRNA quantification; independently replicated by two laboratories

   PMID:40631113 PMID:41213800 PMID:41279844 PMID:41871909

   Open questions at the time

   • Whether the TDMD function and the CRL adaptor function interact or are independently regulated is unknown
   • The full spectrum of miRNAs regulated by the Lrrc58 3′ UTR beyond miR-503-5p is not defined
   • Mechanism linking miR-503-5p to embryonic growth restriction at the target mRNA level is uncharacterized

• Open questions remain about how cysteine is sensed to toggle LRRC58 auto-ubiquitination, whether LRRC58 targets substrates beyond CDO1, and how the dual functions of the LRRC58 locus (CRL adaptor protein and TDMD trigger mRNA) are coordinated in physiology.
• Cysteine-sensing mechanism upstream of LRRC58 stabilization is undefined
• No systematic substrate profiling beyond CDO1
• Interplay between LRRC58 protein function and 3′ UTR TDMD activity unexplored