Ubiquitin, Related Modifiers, & Pathways
Degradation of a protein via the Ubiquitin Proteasome pathway involves two discrete and successive steps: tagging of the substrate protein by the covalent attachment of multiple Ubiquitin molecules (conjugation), and the subsequent degradation of the tagged protein by the 26s proteasome. This classical function is associated with housekeeping roles, including the regulation of protein turnover, and antigenic-peptide generation. More recently, it has become evident that protein modification by Ubiquitin has non-degradative functions, including involvement in DNA repair and histone modification, vesicular trafficking pathways and endocytosis, and viral budding. These activities are dictated by the number of Ubiquitin units attached (mono- versus poly-Ubiquitination) and by the type of Ubiquitin chain linkage that is present. There are three key conjugation enzymes (E1, E2, E3) that function in a hierarchical system that allow Ubiquitin to be activated and become covalently linked to protein substrates. This conjugation process is reversible, and Ubiquitin is removed from substrates by Deubiquitinating enzymes (DUBs).
Although Ubiquitin is the most studied, there is a growing family of Ubiquitin-like proteins (UBLs) that modify cellular targets in a pathway that is parallel to but distinct from that of Ubiquitin. These alternative modifiers include: SUMO, NEDD8, ISG15, APG8, APG12, FAT10, UFM1, URM1, FUB1, and Hub1. Proteins conjugated to UBLs are typically not targeted for degradation by the proteasome, but rather function in diverse regulatory activities including transcription, DNA repair, signal transduction, and autophagy. AutophagyE1 Ubiquitin/Ubl Activating EnzymesE2 Ubiquitin/Ubl Conjugating EnzymesE3 Ubiquitin LigasesDeubiquitinating Enzymes (DUBs)ProteasomeUbiquitinUbiquitin-like Modifiers (UBLs) and Regulators