LRRC58 defines an E3 ubiquitin ligase complex sensitive to cysteine abundance.

Adaptation to fluctuating nutrient supply is essential for organismal survival, but how human cells monitor the abundance of many critical nutrients remains undefined. Characterizing the conditional degradation of CDO1, the critical enzyme responsible for cysteine catabolism, here we identify a Cullin-RING E3 ligase complex defined by the substrate adaptor LRRC58 that is sensitive to cysteine abundance. When cysteine is replete, LRRC58 activity is restrained through 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. CDO1 degradation prevents ferroptotic cell death upon cysteine scarcity, and CDO1 mutations causing 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.