The Ubiquitin Code in the Ubiquitin-Proteasome System and Autophagy

Monoubiquitination has been thought to be non-proteolytic and regulate the interactions and activities of substrates. Emerging evidence shows that monoubiquitin(s) of substrates functions as the degron in the UPS and autophagy. Atypical linkages such as Lys11 and Lys29 linkages serve as proteasomal degrons, alone or in combination with other linkages such as Lys48 and/or Lys63. Ubiquitin chains such as Lys63 linkages mediate autophagic protein quality control through the recognition by autophagic adaptors such as p62. Ubiquitin chains, mainly Lys63 linkages, function as a trans-degron for autophagic removal of cellular organelles and structures in mitophagy, pexophagy, ER-phagy, ribophagy, and lipophagy. Ubiquitin is the substrate of small-molecule post-translational modifications such as phosphorylation and acetylation. The conjugation of the 76 amino acid protein ubiquitin to other proteins can alter the metabolic stability or non-proteolytic functions of the substrate. Once attached to a substrate (monoubiquitination), ubiquitin can itself be ubiquitinated on any of its seven lysine (Lys) residues or its N-terminal methionine (Met1). A single ubiquitin polymer may contain mixed linkages and/or two or more branches. In addition, ubiquitin can be conjugated with ubiquitin-like modifiers such as SUMO or small molecules such as phosphate. The diverse ways to assemble ubiquitin chains provide countless means to modulate biological processes. We overview here the complexity of the ubiquitin code, with an emphasis on the emerging role of linkage-specific degradation signals (degrons) in the ubiquitin-proteasome system (UPS) and the autophagy-lysosome system (hereafter autophagy). The conjugation of the 76 amino acid protein ubiquitin to other proteins can alter the metabolic stability or non-proteolytic functions of the substrate. Once attached to a substrate (monoubiquitination), ubiquitin can itself be ubiquitinated on any of its seven lysine (Lys) residues or its N-terminal methionine (Met1). A single ubiquitin polymer may contain mixed linkages and/or two or more branches. In addition, ubiquitin can be conjugated with ubiquitin-like modifiers such as SUMO or small molecules such as phosphate. The diverse ways to assemble ubiquitin chains provide countless means to modulate biological processes. We overview here the complexity of the ubiquitin code, with an emphasis on the emerging role of linkage-specific degradation signals (degrons) in the ubiquitin-proteasome system (UPS) and the autophagy-lysosome system (hereafter autophagy).