LRRC58

LRRC58 is the cysteine-responsive substrate adaptor of a CUL2/CUL5-based cullin-RING E3 ubiquitin ligase that couples sulfur amino acid sensing to the proteasomal control of cysteine catabolism (PMID:40963025, PMID:42098103). It recruits cysteine dioxygenase CDO1 — the rate-limiting enzyme of the cysteine-to-taurine shunt — and positions it for ubiquitylation at Lys8; the regulatory logic is set by cysteine availability, with cysteine repletion driving LRRC58 auto-ubiquitination and turnover while cysteine starvation stabilizes LRRC58 to enforce CDO1 degradation (PMID:40963025, PMID:42098103). Through this axis LRRC58 conserves cysteine, and its loss in hepatocytes stabilizes CDO1, raises cysteine-to-taurine flux, and lowers hepatic cholesterol, linking cysteine catabolism to liver cholesterol handling (PMID:40963025). The adaptor function is conserved to C. elegans, where the ortholog lrr-2 post-translationally regulates cysteine dioxygenase and sulfur metabolism (PMID:39786993). Independently of its protein product, the Lrrc58 3' UTR acts as a TDMD trigger RNA: it base-pairs with miR-503-5p to drive ZSWIM8-dependent decay of the miRNA, a function required for normal embryonic growth (PMID:41213800, PMID:41871909).

1. 2025 High

   Establishing LRRC58 as a substrate adaptor of a cullin-RING ligase defined a molecular machine for regulated CDO1 destruction and revealed cysteine itself as the upstream regulatory signal.

   Evidence Quantitative covariation proteomics, active CRL profiling, biochemical reconstitution, cryo-EM, and hepatocyte depletion in mice

   PMID:40963025 PMID:42098103

   Open questions at the time

   • The biochemical mechanism by which cysteine abundance triggers LRRC58 auto-ubiquitination is not defined
   • Whether CUL2 versus CUL5 usage is context-dependent is not resolved
2. 2026 High

   Cryo-EM and saturation mutagenesis pinpointed the CDO1-LRRC58 interface and the Lys8 ubiquitylation site, explaining how disease-associated CDO1 mutants escape recognition.

   Evidence Cryo-EM structural determination, reconstitution, saturation mutagenesis stability profiling, and VHL-based degrader assays

   PMID:42098103

   Open questions at the time

   • Structural basis for cysteine-dependent LRRC58 stability switching is not captured
   • Whether other substrates besides CDO1 engage the same interface is unknown
3. 2025 High

   Hepatocyte-specific depletion connected the LRRC58-CDO1 axis to whole-organ physiology, showing cysteine catabolic flux governs hepatic cholesterol levels.

   Evidence Hepatocyte-specific LRRC58 depletion in mice with metabolite flux and cholesterol measurements

   PMID:40963025

   Open questions at the time

   • Mechanistic link between taurine production and cholesterol handling is not detailed
   • Tissue specificity of this phenotype beyond liver is unaddressed
4. 2025 Medium

   C. elegans genetics established that adaptor-mediated control of cysteine dioxygenase is evolutionarily conserved and feeds into H2S/sulfur metabolism.

   Evidence Forward genetic selection, epistasis with cdo-1 and cth-2, and exogenous H2S rescue in C. elegans

   PMID:39786993

   Open questions at the time

   • Whether lrr-2 acts via an orthologous CRL complex in worms was not biochemically confirmed
   • Single-lab genetic study
5. 2025 Medium

   Saturation mutagenesis and cysteine-deprivation cell-death assays linked LRRC58-mediated CDO1 turnover to ferroptosis prevention and to dominant-active human CDO1 disease alleles.

   Evidence Saturation mutagenesis stability profiling, cell-death assays under cysteine deprivation, and interface modeling (preprint)

   PMID:bio_10.1101_2025.09.23.678073

   Open questions at the time

   • Preprint not yet peer-reviewed
   • Direct demonstration that CDO1 disease mutants cause neurodevelopmental phenotypes via ferroptosis is incomplete
6. 2026 High

   A distinct, RNA-level function emerged: the Lrrc58 3' UTR is a TDMD trigger for miR-503-5p driving ZSWIM8-dependent miRNA decay required for embryonic growth.

   Evidence AGO-CLASH, CRISPR deletion of the trigger site in mice, miRNA abundance and genetic rescue experiments

   PMID:41213800 PMID:41871909

   Open questions at the time

   • Whether the protein-coding and TDMD functions of the Lrrc58 locus are coordinately regulated is unknown
   • The growth-restriction mechanism downstream of miR-503-5p is not mapped

• How cysteine concentration is biochemically transduced into LRRC58 stability, and whether the CRL adaptor has substrates beyond CDO1, remain open.
• No direct cysteine-sensing mechanism for LRRC58 stability identified
• Substrate repertoire beyond CDO1 uncharacterized
• Relationship between the protein-coding and trigger-RNA roles of the locus undefined