The proteolysis-assisted protein surveillance control system guards the proteome from potentially detrimental aberrant proteins. How miscellaneous defective proteins are specifically recognized and eliminated are fundamental questions. We revealed a C-degron pathway 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. We showed that the C-degron pathway safeguards the fidelity of the selenoproteome, clears faulty segregated proteins, and removes the cleavage products of proteases. We showcased two modes of collaborative actions between N-degron and C-degron pathways in protein elimination. Importantly, canonical proteomes and coronaviruses have adapted to circumvent destruction by the C-degron pathway, suggesting proteolysis-based immunity as a constraint for proteome evolution. Our work highlights the importance of protein termini for protein surveillance, and the relationship between canonical proteome and protein degradation pathways.