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Review
. 2013 Jan 18;112(2):367-81.
doi: 10.1161/CIRCRESAHA.112.268706.

Posttranslational modification and quality control

Xuejun Wang  1 , J Scott Pattison, Huabo Su
Affiliations
Review

Posttranslational modification and quality control

Xuejun Wang et al. Circ Res. .

Abstract

Protein quality control functions to minimize the level and toxicity of misfolded proteins in the cell. Protein quality control is performed by intricate collaboration among chaperones and target protein degradation. The latter is performed primarily by the ubiquitin-proteasome system and perhaps autophagy. Terminally misfolded proteins that are not timely removed tend to form aggregates. Their clearance requires macroautophagy. Macroautophagy serves in intracellular quality control also by selectively segregating defective organelles (eg, mitochondria) and targeting them for degradation by the lysosome. Inadequate protein quality control is observed in a large subset of failing human hearts with a variety of causes, and its pathogenic role has been experimentally demonstrated. Multiple posttranslational modifications can occur to substrate proteins and protein quality control machineries, promoting or hindering the removal of the misfolded proteins. This article highlights recent advances in posttranslational modification-mediated regulation of intracellular quality control mechanisms and its known involvement in cardiac pathology.

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Figures

Figure 1
Figure 1. An illustration of protein quality control in the cell
Chaperones help fold nascent polypeptides, unfold misfolded proteins and refold them, and channel 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. Aggregated proteins can be selectively targeted by macroautophagy to, and degraded by, the lysosome.
Figure 2
Figure 2. A prevalent model for the regulation of cullin RING ligases (CRLs) by neddylation-deneddylation
Analogous to ubiquitination, neddylation covalently attaches NEDD8 to a lysine residue of a target protein (e.g., cullin). It is catalyzed by NEDD8 activating enzyme (NAE), conjugating enzyme (Ubc12), and presumably specific ligases (NEDD8 E3). As illustrated in the SCF (Skp1-Cullin1-Fbox) ubiquitin (Ub) ligase, cullin neddylation displaces CAND1 (cullin-associated NEDD8-dissociated protein 1), which triggers the assembly of an active CRL complex and brings the adaptor-bound substrate to a close proximity to Ub-charged E2 and allows efficient transfer of the Ub from E2 to the substrate. Deneddylation counters neddylation and is done by deneddylases. The COP9 signalosome (CSN) is the deneddylase responsible for cullin deneddylation. Cullin deneddylation triggers the disassembly of the CRL-substrate complex, releases ubiquitinated substrates, and recycles NEDD8.
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