Ubiquitin and Ubiquitin-like proteins in cardiac disease and protection

Abstract

Post-translational modification represents an important mechanism to regulate protein function in cardiac cells. Ubiquitin (Ub) and ubiquitin-like proteins (UBLs) are a family of protein modifiers that share a certain extent of sequence and structure similarity. Conjugation of Ub or UBLs to target proteins is dynamically regulated by a set of UBL-specific enzymes and modulates the physical and physiological properties of protein substrates. Ub and UBLs control a strikingly wide spectrum of cellular processes and not surprisingly are involved in the development of multiple human diseases including cardiac diseases. Further identification of novel UBL targets will expand our understanding of the functional diversity of UBL pathways in physiology and pathology. Here we review recent findings on the mechanisms, proteome and functions of a subset of UBLs and highlight their potential impacts on the development and progression of various forms of cardiac diseases.

Keywords: NEDD8; SUMO; Ubiquitin; cardiomyopathies; proteasome; ubiquitin-like proteins..

Figure 1. A list of the ubiquitin (Ub) and ubiquitin-like (UBL protein) pathways

Ub and UBLs (SUMO, NEDD8, ISG15, FAT10 and Ufm1) are covalently conjugated to protein substrates. Three types of enzymes – E1, E2 and E3 – mediate the conjugation reactions. The conjugation process can be reversed by de-conjugation enzymes. Distinct sets of conjugation and deconjugation enzymes for individual protein modifiers and their substrates are depicted.

Figure 2. Overview of the ubiquitin proteasome system-mediated proteolysis

E1 activating enzyme activates Ub by forming a thioester bond (red) in an ATP-dependent manner. E2 conjugating enzymes accept the activated Ub through transthiolation from E1. E3 ligases then fuse the activated Ub with the lysine residue (K) of the substrates by forming an isopeptide bond. Multiple cycles of conjugation process lead to the attachment of a chain of Ub to the substrates. Polyubiquitinated proteins are recognized and degraded by the 26S proteasome, which consists of a 20S core particle and two 19S regulatory particles at each end of the 20S. Deubiquitinases (DUBs) remove Ub from the ubiquitinated proteins and prevent their degradation by the proteasome.

Figure 3. Role of insufficient ubiquitin-proteasome system (UPS) function in the development of cardiac diseases

Expression of misfolded proteins, genetic ablations of Ub ligases and impairment of proteasome function cause cardiomyopathies or sensitize the heart to cardiac stresses, whereas enhancement of proteasome function shows cardioprotection to proteinopathy and I/R injury. The notion is in agreement with clinic reports of cardiotoxicity in cancer patients receiving proteasome inhibitors. See the main text for more details. KO, knockout. mPSMB5, dominant-negative PSMB5 mutant. PA28αOE, PA28α overexpression. PKG, protein kinase G.