Oxidation‐Induced C‐Terminal Amidation Marks Proteins for Degradation

ABSTRACT Proteostasis hinges on the precise recognition and elimination of damaged proteins through the ubiquitin–proteasome system (UPS), where E3 ubiquitin ligases recognize degradation signals, or degrons. While degrons have traditionally been viewed as genetically encoded or enzymatically generated motifs, emerging evidence suggests that nonenzymatic chemical damage can also create functional degradation signals. Oxidative stress‐induced peptide backbone fragmentation, including hydroxyl radical‐mediated cleavage, generates proteins bearing C‐terminal amide groups (CTAPs), a chemically derived degron class recognized by the SCF–FBXO31 E3 ligase complex. Genome‐wide CRISPR screening identified FBXO31 as a selective CTAP reader required for ubiquitination and proteasomal clearance of amidated substrates. Disruption of this pathway impairs proteostasis and, in disease‐associated FBXO31 mutants, promotes aberrant degradation of non‐amidated proteins such as SUGT1, contributing to cytotoxicity and neurodevelopmental dysfunction. Collectively, these findings redefine degron biology via establishing chemically induced modified amino acid degrons (MAADs) as mechanistic links between oxidative damage and selective protein degradation.