The Ubiquitin Code in Disease Pathogenesis and Progression: Composition, Characteristics and its Potential as a...

Conjugation of substrate proteins with ubiquitin (Ub), a 76 amino acid protein, was discovered as the first major translational modification responsible for protein degradation. Ubiquitination occurs as a cascade among ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin ligases (E3) enzymes that transfer and covalently conjugate Ub to the lysine (Lys) residue and α-amino group in methionine (Met) residues of substrates. Following the initial conjugation, Ub itself then undergoes ubiquitination via its seven lysine residues (K6, K11, K27, K29, K33, K48, and K63) and N-terminal methionine (M1). These possible sites of Ub polymerization/assembly result in a significantly diverse and numerous set of linkage types and lengths, including homotypic, mixed and/or branched chains, which provoke distinct cellular responses via their proteolytic and non-proteolytic functions. We overview here the multiplicity of ubiquitin code with a particular focus on linkage-specific roles in biological processes, especially in the pathogenesis and progression of diseases such as cancer, neurodegeneration, and immune disorders. We will also discuss the possibility and ongoing efforts of modulating the ubiquitin code as a therapeutic strategy in drug development, including targeted protein degradation (TPD).