OUP user menu


Back to Image Gallery

A schematic illustration of protein quality control (PQC) in the cell

Su H & Wang X Cardiovasc Res (2010) 85(2): 253-262 first published online August 20, 2009 doi:10.1093/cvr/cvp287 - Click here to view the abstract

PQC is carried out by chaperones, the ubiquitin proteasome system (UPS), and the autophagy-lysosome pathway. Chaperones facilitate the folding of nascent polypeptides and the unfolding/refolding of misfolded proteins, prevent the misfolded proteins from aggregating, and escort terminally misfolded proteins for degradation by the UPS. The UPS degrades misfolded proteins and unneeded native proteins in the cell through two general steps: first, covalent attachment of ubiquitin to a target protein by a cascade of chemical reactions catalysed by the ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin ligase (E3); second, the degradation of the target protein by the proteasome. The autophagy-lysosomal pathway helps remove protein aggregates formed by the misfolded proteins that have escaped from the surveillance of chaperones and the UPS. Protein aggregates or defective organelles are first segregated by an isolated double membrane (phagophore) to form autophagosomes, which later fuse with lysosomes to form autophagolysosomes, where the segregated content is degraded by lysosomal hydrolases. p62/SQSTM1 and NBR1 (neighbour of BRCA1 gene 1) may mediate the activation of autophagy by aggregated ubiquitinated proteins. The legend for symbols used is shown in the box at the lower left.

The ubiquitin-proteasome system

Dantuma NP & Lindsten K Cardiovasc Res (2010) 85(2): 263-271 first published online July 25, 2009 doi:10.1093/cvr/cvp255 - Click here to view the abstract

Free ubiquitin proteins are generated from the processing of ubiquitin precursors or ubiquitin chains by deubiquitylation enzymes (DUBs). An enzymatic cascade involving the E1 (ubiquitin activase), E2 (ubiquitin conjugase), and E3 (ubiquitin ligase) enzymes covalently conjugates ubiquitin chains to lysine residues in target proteins. Proteins deemed for degradation are singled out by E3 enzymes through the presence of a degradation signal (degron). The ubiquitylated substrate is recognized by a large proteolytic complex, the proteasome. The proteasome contains of 19S regulatory particles and the 20S core particle, which contains several proteolytic active subunits. The 19S regulatory particle binds, deubiquitylates, unfolds, and translocates the substrate into the proteolytic chamber of the 20S particle where the protein is degraded into short peptide fragments.


The nonsense-mediated mRNA decay – a mRNA surveillance pathway

Carrier L et al. Cardiovasc Res (2010) 85(2): 330-338 first published online July 17, 2009 doi:10.1093/cvr/cvp247 - Click here to view the abstract


MYBPC3 is one of the most frequently mutated genes in hypertrophic cardiomyopathy (HCM). Most mutations result in a frameshift and a premature termination codon (PTC) and should produce truncated proteins, which were never detected in myocardial tissue of patients. Recent data showed that the nonsense-mediated mRNA decay (NMD) is involved in the degradation of nonsense mRNA in a mouse model of HCM (Vignier, Schlossarek et al., Circ Res 2009). NMD is an evolutionarily conserved pathway existing in all eukaryotes that detects and eliminates PTC-containing transcripts. NMD apparently evolved to protect the organism from the deleterious dominant-negative or gain-of-function effects of resulting truncated proteins.

(A) NMD occurs when a PTC is located more than 50–55 nucleotides (nt) upstream of the last exon–exon junction within the mRNA (green region), whereas mRNAs with PTCs downstream of this boundary (red region) escape NMD. (B) During pre-mRNA splicing, exon junction complexes (EJC) are deposited upstream of every exon–exon junction. In normal transcripts, EJCs are displaced by the ribosome during the pioneer round of translation, and translation stops when the ribosome reaches the normal stop codon. In contrast, in PTC-bearing mRNAs, the ribosome is blocked at the PTC and the EJC downstream of the PTC remains associated with the mRNA. This results in attachment of the SURF complex to the ribosome. Subsequent phosphorylation of UPF1 by SMG-1 drives dissociation of eRF1 and eRF3 and binding of SMG7. Ultimately, the mRNA is degraded by different pathways including decapping or deadenylation.


The role of the protein degradation systems in viral myocarditis leading to dilated cardiomyopathy

Luo H et al. Cardiovasc Res (2010) 85(2): 347-356 first published online July 3, 2009 doi:10.1093/cvr/cvp225 - Click here to view the abstract

Viral myocarditis is an inflammatory disease of the myocardium caused by virus infection. The disease progression occurs in three distinct stages: viral infection, immune response, and cardiac remodelling. Recent evidence suggests that the host proteolytic systems play crucial roles in the regulation of the pathogenesis of viral myocarditis in all three stages. During the viral infection stage, the virus evolves different strategies to utilize the host ubiquitin/proteasome system and the autophagy machinery to facilitate its replication. At the immune response stage, viral infection induces the formation of an immunoproteasome to increase MHC class I antigen presentation. Meanwhile, production of pro-inflammatory cytokines is enhanced, partially through the ubiquitin/proteasome system-mediated NFκB activation. Autophagy may also contribute to immune-mediated pathogenesis by modulating MHC class II antigen presentation. During the cardiac remodelling phase, increased accumulation of abnormal ubiquitin-protein conjugates/aggregates and elevated oxidative stress lead to the eventual impairment of the ubiquitin/proteasome function, subsequently resulting in abnormal regulation of contractile apparatus expression and also triggering apoptosis and autophagic cell death. As a result of myocyte loss and decreased contractile properties, the left ventricle of the heart begins to dilate to compensate for impaired cardiac function.

Back to Image Gallery