Ubiquitin and Ubiquitin-like Proteins in Cancer, Neurodegenerative Disorders, and Heart Diseases

Abstract

Post-translational modification (PTM) is an essential mechanism for enhancing the functional diversity of proteins and adjusting their signaling networks. The reversible conjugation of ubiquitin (Ub) and ubiquitin-like proteins (Ubls) to cellular proteins is among the most prevalent PTM, which modulates various cellular and physiological processes by altering the activity, stability, localization, trafficking, or interaction networks of its target molecules. The Ub/Ubl modification is tightly regulated as a multi-step enzymatic process by enzymes specific to this family. There is growing evidence that the dysregulation of Ub/Ubl modifications is associated with various diseases, providing new targets for drug development. In this review, we summarize the recent progress in understanding the roles and therapeutic targets of the Ub and Ubl systems in the onset and progression of human diseases, including cancer, neurodegenerative disorders, and heart diseases.

Keywords: disease association and progression; post-translational modification; ubiquitin; ubiquitin-like proteins; ubiquitin-proteasome system.

Figure 1

Biochemical and Structural Features of Ubiquitin & Ubiquitin-like Proteins. (A) Main steps in the substrate modification process by Ub. The β-grasp globular fold structure of Ub is shown in the circle. (B) Examples of structural domains within human type I and type II Ub family members. DUB, de-ubiquitinating enzymes; FAT10, HLA-F-adjacent transcript 10; ISG15, Interferon-stimulated gene 15; NEDD8, Neural precursor cell-expressed developmentally down-regulated gene 8; NUB1, NEDD8 ultimate buster 1; OASL, 2′-5′-oligoadenylate synthetase-like protein; SUMO1, small ubiquitin-like modifier 1; Ub, ubiquitin; UBL, ubiquitin-like domain; UBA, ubiquitin-associated domain. Figure 1A adapted from “ubiquitination”, by BioRender.com (accessed on 1 March 2022). Retrieved from https://app.biorender.com/biorender-templates. Agreement number is OU23V77K75.

Figure 2

The ubiquitin-proteasome system (UPS). In step 1, ubiquitin is activated by a ubiquitin activating enzyme (E1). In step 2, activated ubiquitin (Ub) is transferred to a ubiquitin conjugating enzyme (E2). In step 3, ubiquitin is transferred from E2 to a specific target (substrate) lysine to form a covalent bond. This process is catalyzed by E3 ubiquitin ligase. In step 4, repeated ubiquitin conjugation generates a poly-ubiquitin chain. In step 5, the ubiquitinated target (e.g., canonical K48 linkage) is recognized, unfolded, and digested by the 26S proteasome. In step 6, Deubiquitinating (DUB) enzymes remove covalently linked ubiquitin moieties from ubiquitin-ubiquitin and ubiquitin-protein conjugates. These enzymes also process ubiquitin precursors to generate free (un-anchored) ubiquitin pools. The free ubiquitin can be further reused. Inhibitors of various UPS components are being developed clinically for the treatment of cancer and neurodegenerative diseases.

Figure 3

Small molecules targeting the SUMO pathway. In step 1: SUMO E1 (SAE1/SAE2 heterodimer) activates mature SUMO through an ATP-dependent reaction. SAE1 catalyzes adenylation of the C-terminus of SUMO to form a SUMO-AMP intermediate, which then transfers SUMO to SAE2 and forms a thioester bond. In step 2: SUMO is transferred from SAE2 to SUMO E2 (UBC9), which in turn forms a thioester bond. In steps 3 and 4: UBC9 catalyzes the formation of an isopeptide bond between the C-terminal glycine of SUMO and a lysine residue on the substrate. Certain SUMO E3 ligases are often involved in this process. In step 5: SUMO is removed from the lysine residue of the target proteins by a de-SUMOylation enzyme (DS), such as SENP, sentrin-specific protease. SENP also catalyzes SUMO maturation by cleaving the precursor SUMO at C-terminus, exposing two glycine residues required for conjugation.