Regulation of cardiac proteasomes by ubiquitination, SUMOylation, and beyond

Abstract

The ubiquitin-proteasome system (UPS) is the major intracellular degradation system, and its proper function is critical to the health and function of cardiac cells. Alterations in cardiac proteasomes have been linked to several pathological phenotypes, including cardiomyopathies, ischemia-reperfusion injury, heart failure, and hypertrophy. Defects in proteasome-dependent cellular protein homeostasis can be causal for the initiation and progression of certain cardiovascular diseases. Emerging evidence suggests that the UPS can specifically target proteins that govern pathological signaling pathways for degradation, thus altering downstream effectors and disease outcomes. Alterations in UPS-substrate interactions in disease occur, in part, due to direct modifications of 19S, 11S or 20S proteasome subunits. Post-translational modifications (PTMs) are one facet of this proteasomal regulation, with over 400 known phosphorylation sites, over 500 ubiquitination sites and 83 internal lysine acetylation sites, as well as multiple sites for caspase cleavage, glycosylation (such as O-GlcNAc modification), methylation, nitrosylation, oxidation, and sumoylation. Changes in cardiac proteasome PTMs, which occur in ischemia and cardiomyopathies, are associated with changes in proteasome activity and proteasome assembly; however several features of this regulation remain to be explored. In this review, we focus on how some of the less common PTMs affect proteasome function and alter cellular protein homeostasis.

Ablation of Adenosine Monophosphate-Activated Protein Kinase α1 in Vascular Smooth Muscle Cells Promotes Diet-Induced Atherosclerotic Calcification In Vivo

“…33 We checked whether SUMOylation of Runx2 may affect its stability and degradation. We silenced protein inhibitor of activated STAT-1 (PIAS1), the SUMO E3-ligase of Runx2, 32 and ubiquitin conjugating enzyme 9 (UBC9), the unique E2 SUMOylation ligase, 34 to suppress Runx2 SUMOylation.…”

The Ubiquitin-Proteasome System (UPS) as a Cancer Drug Target: Emerging Mechanisms and Therapeutics

“…Despite this brief didactic view of the UPS classifying enzymes, cofactors and substrates, the system is a lot more complex than presented here, and there is still a distinct lack of knowledge with respect to its overall organization. For instance, it is well known that under certain circumstances several modifying/de-modifying enzymes can act on distinct members of the ubiquitin family (Leidecker et al 2012 ), that proteasome subunits can be substrates of ubiquitin and ubiquitin-like molecules (Cui et al 2014 ), or that the proteasome can also drive proteolysis in the absence of protein modifi cation (Erales and Coffi no 2014 ). Although most of the functional outcomes of recent fi ndings are not completely understood, it becomes clear that simply targeting a single enzymesubstrate pair will be diffi cult.…”

Characterizing the Dynamics of Proteasome Complexes by Proteomics Approaches

“…The vast amount of information gained by proteomics studies has dramatically enhanced our current understanding of the UPS on a more systems level. The PTMs of proteasomes and their roles in regulating the proteasome function has been nicely reviewed recently by Cui et al (16). Specific aspects on the phosphorylation and oxidation of proteasome complexes in cardiac tissues and their impact on proteasome structures and activities are described by Drews (18) and Soriano et al (69), respectively, in this Forum.…”

“…Along with b1i and b2i, they can replace the three canonical catalytic b1, b2, and b5 subunits and form thymoproteasomes that are critical for thymic education. Apart from subunit composition, proteasomes can be further modulated by posttranslational modifications (PTMs) and proteasome interacting proteins (PIPs) (1,11,16,20,24,65,79). It is evident that proteasome complexes in eukaryotic cells represent a dynamic and heterogeneous population, whose proteomes and functions can change depending on cell or tissue types, subcellular localization, and in response to extracellular cues (Fig.…”