Proteasomal and lysosomal protein degradation and heart disease

Abstract

In the cell, the proteasome and lysosomes represent the most important proteolytic machineries, responsible for the protein degradation in the ubiquitin-proteasome system (UPS) and autophagy, respectively. Both the UPS and autophagy are essential to protein quality and quantity control. Alterations in cardiac proteasomal and lysosomal degradation are remarkably associated with most heart disease in humans and are implicated in the pathogenesis of congestive heart failure. Studies carried out in animal models and in cell culture have begun to establish both sufficiency and, in some cases, the necessity of proteasomal functional insufficiency or lysosomal insufficiency as a major pathogenic factor in the heart. This review article highlights some recent advances in the research into proteasome and lysosome protein degradation in relation to cardiac pathology and examines the emerging evidence for enhancing degradative capacities of the proteasome and/or lysosome as a new therapeutic strategy for heart disease. This article is part of a Special Issue entitled "Protein Quality Control, the Ubiquitin Proteasome System, and Autophagy".

Keywords: Autophagy; Heart disease; Lysosome; Proteasome; Ubiquitin.

Figure 1. A schematic illustration of cellular mechanisms protecting against proteotoxicity

Chaperones help fold nascent polypeptides, unfold misfolded proteins and refold them, and escort terminally misfolded proteins for degradation by the ubiquitin-proteasome system (UPS) or chaperone-mediated autophagy (CMA). When escaped from targeted degradation, misfolded proteins form aggregates via hydrophobic interactions. The higher order of aggregation is likely promoted by ubiquitin binding proteins and trafficking via microtubules. Aggregated proteins can be selectively targeted by macroautophagy to, and degraded by, the lysosome. (Modified from Wang et al. [29])

Figure 2. Ubiquitin-proteasome system-mediated proteolysis

A substrate protein molecule is first covalently tagged with a chain of ubiquitin (Ub) protein molecules, a process known as ubiquitination which is performed by a cascade of enzymatic reactions catalyzed sequentially by E1 (Ub activating enzyme), E2 (Ub conjugating enzyme), and E3 (Ub ligase). The conjugated Ub can be removed from the substrate via a process known as deubiquitination, which counters ubiquitination and is performed by deubiquitinating enzymes (DUBs). Ubiquitinated substrates may be directly recognized and bound by the 19S proteasome, but often require extraproteasomal Ub receptor proteins (i.e., UBA-UBL proteins) to be delivered to, and degraded by, the 26S proteasome (26S). (Adopted from Wang and Terpstra [4])

Figure 3. Aberrant aggregation of misfolded proteins in cardiomyocytes

An HA-epitope tagged missense (R120G) mutant CryAB (HA-CryAB^R120G) was expressed in cultured neonatal rat cardiomyocytes (NRCMs) via adenoviral gene delivery. At 6 days after the viral infection, the cells were fixed with 3.8% paraformaldehyde and subject to immunofluorescence staining for the HA tag (green). The nuclei were stained blue using DAPI. The stained NRCMs were imaged with an epi-fluorescence microscope. Four main distribution patterns of CryAB^R120G proteins were observed and are annotated according to our perception of their representation of the different stages of the aberrant protein aggregation in the cell. Aberrant protein aggregation impairs the UPS, which in turn allows more of the misfolded proteins undergo aberrant aggregation, forming a vicious cycle. Scale bar=25 μm