The proteolysis-assisted protein quality control system guards the proteome from potentially detrimental aberrant proteins. How miscellaneous defective proteins are specifically eliminated and which molecular characteristics direct them for removal are fundamental questions. We reveal a mechanism, DesCEND (destruction via C-end degrons), by which CRL2 ubiquitin ligase uses interchangeable substrate receptors to recognize the unusual C termini of abnormal proteins (i.e., C-end degrons). C-end degrons are mostly less than ten residues in length and comprise a few indispensable residues along with some rather degenerate ones. The C-terminal end position is essential for C-end degron function. Truncated selenoproteins generated by translation errors and the USP1 N-terminal fragment from post-translational cleavage are eliminated by DesCEND. DesCEND also targets full-length proteins with naturally occurring C-end degrons. The C-end degron in DesCEND echoes the N-end degron in the N-end rule pathway, highlighting the dominance of protein “ends” as indicators for protein elimination. Display omitted •CRL2 ubiquitin ligase functions in protein quality control•CRL2 recognizes the unusual C-termini of aberrant proteins (i.e., C-end degrons)•CRL2 recognizes various C-end degrons through interchangeable substrate receptors•CRL2 also targets full-length proteins with naturally occurring C-end degrons Lin et al. uncover a protein degradation mechanism, DesCEND (destruction via C-end degrons), by which CRL2 ubiquitin ligase recognizes and eliminates proteins with exposed C-end degrons through interchangeable substrate receptors. The C-end degron in DesCEND echoes the N-end degron in the N-end rule pathway, highlighting the dominance of protein “ends” in directing protein elimination.