LRRC58 defines an E3 ubiquitin ligase complex sensitive to cysteine abundance
11 affiliations
- 1Cambridge Institute for Therapeutic Immunology and Infectious Disease, Department of Medicine, University of Cambridge, Puddicombe Way, Cambridge, UK
- 2CITIID, University of Cambridge
- 3Centre for Targeted Protein Degradation, School of Life Sciences, University of Dundee, Dundee, UK
- 4Centre for Targeted Protein Degradation, University of Dundee
- 5The Gurdon Institute, University of Cambridge, Cambridge, UK; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
- 6Gurdon Institute, University of Cambridge
- 7Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, Cambridge, UK
- 8CIMR, University of Cambridge
- 9The Gurdon Institute, University of Cambridge, Cambridge, UK; Department of Biochemistry, University of Cambridge, Cambridge, UK
- 10Cambridge Institute for Therapeutic Immunology and Infectious Disease, Department of Medicine, University of Cambridge, Puddicombe Way, Cambridge, UK; NHS Blood and Transplant, Cambridge, UK
- 11Cambridge Institute for Therapeutic Immunology and Infectious Disease, Department of Medicine, University of Cambridge, Puddicombe Way, Cambridge, UK. Electronic address: [email protected]
Abstract
Adaptation to fluctuating nutrient supply is essential for organismal survival, but how cells sense and respond to changes in the abundance of many critical nutrients remains undefined. One such example is the amino acid cysteine, whose reactive thiol group is exploited for diverse cellular functions. Here, by characterizing the machinery required for the conditional degradation of cysteine dioxygenase type I (CDO1), the critical enzyme responsible for cysteine catabolism, we identify a Cul2 E3 ligase complex containing the uncharacterized substrate adaptor LRRC58 that is sensitive to cysteine abundance. When cysteine is replete, LRRC58 activity is restrained through auto-ubiquitination and proteasomal degradation; upon cysteine deprivation, LRRC58 is stabilized to permit CDO1 degradation. Through saturation mutagenesis stability profiling, we systematically validate a structural model of the CDO1-LRRC58 interaction and identify residues at the LRRC58 C-terminus required for cysteine-dependent instability. The LRRC58-mediated degradation of CDO1 is essential to prevent ferroptotic cell death under conditions of cysteine scarcity, and mutations in CDO1 which cause neurodevelopmental defects in humans encode dominant-active proteins refractory to LRRC58 recognition. Altogether, these data reveal the CDO1-LRRC58 axis as a critical regulator of cysteine homeostasis that safeguards neural development.
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BibTeX
@article{ramage2026lrrc58,
title = {{LRRC58 defines an E3 ubiquitin ligase complex sensitive to cysteine abundance}},
author = {Dylan E. Ramage and Lianne H. E. Wieske and Charlotte Crowe and Jens Bager Christensen and Theo A. von Wilmowski and Zoe Bannister and Drew W. Grant and Mark A. Nakasone and Kevin Haubrich and Mark Dorward and Iva A. Tchasovnikarova and Michael P. Weekes and Nicholas J. Matheson and N. Sumru Bayin and Alessio Ciulli and Richard T. Timms},
journal = {Molecular Cell},
year = {2026},
month = jun,
doi = {10.1016/j.molcel.2026.06.014},
url = {https://doi.org/10.1016/j.molcel.2026.06.014},
note = {CC BY},
}
RIS
TY - JOUR
TI - LRRC58 defines an E3 ubiquitin ligase complex sensitive to cysteine abundance
AU - Dylan E. Ramage
AU - Lianne H. E. Wieske
AU - Charlotte Crowe
AU - Jens Bager Christensen
AU - Theo A. von Wilmowski
AU - Zoe Bannister
AU - Drew W. Grant
AU - Mark A. Nakasone
AU - Kevin Haubrich
AU - Mark Dorward
AU - Iva A. Tchasovnikarova
AU - Michael P. Weekes
AU - Nicholas J. Matheson
AU - N. Sumru Bayin
AU - Alessio Ciulli
AU - Richard T. Timms
PY - 2026
DA - 2026/06/19
JO - Molecular Cell
DO - 10.1016/j.molcel.2026.06.014
UR - https://doi.org/10.1016/j.molcel.2026.06.014
AB - Adaptation to fluctuating nutrient supply is essential for organismal survival, but how cells sense and respond to changes in the abundance of many critical nutrients remains undefined. One such example is the amino acid cysteine, whose reactive thiol group is exploited for diverse cellular functions. Here, by characterizing the machinery required for the conditional degradation of cysteine dioxygenase type I (CDO1), the critical enzyme responsible for cysteine catabolism, we identify a Cul2 E3 ligase complex containing the uncharacterized substrate adaptor LRRC58 that is sensitive to cysteine abundance. When cysteine is replete, LRRC58 activity is restrained through auto-ubiquitination and proteasomal degradation; upon cysteine deprivation, LRRC58 is stabilized to permit CDO1 degradation. Through saturation mutagenesis stability profiling, we systematically validate a structural model of the CDO1-LRRC58 interaction and identify residues at the LRRC58 C-terminus required for cysteine-dependent instability. The LRRC58-mediated degradation of CDO1 is essential to prevent ferroptotic cell death under conditions of cysteine scarcity, and mutations in CDO1 which cause neurodevelopmental defects in humans encode dominant-active proteins refractory to LRRC58 recognition. Altogether, these data reveal the CDO1-LRRC58 axis as a critical regulator of cysteine homeostasis that safeguards neural development.
SN - 1097-2765
SN - 1097-4164
ER -