Parkin-mediated ubiquitin signalling in aggresome formation and autophagy

Abstract

Understanding how cells handle and dispose of misfolded proteins is of paramount importance because protein misfolding and aggregation underlie the pathogenesis of many neurodegenerative disorders, including PD (Parkinson's disease) and Alzheimer's disease. In addition to the ubiquitin-proteasome system, the aggresome-autophagy pathway has emerged as another crucial cellular defence system against toxic build-up of misfolded proteins. In contrast with basal autophagy that mediates non-selective, bulk clearance of misfolded proteins along with normal cellular proteins and organelles, the aggresome-autophagy pathway is increasingly recognized as a specialized type of induced autophagy that mediates selective clearance of misfolded and aggregated proteins under the conditions of proteotoxic stress. Recent evidence implicates PD-linked E3 ligase parkin as a key regulator of the aggresome-autophagy pathway and indicates a signalling role for Lys(63)-linked polyubiquitination in the regulation of aggresome formation and autophagy. The present review summarizes the current knowledge of the aggresome-autophagy pathway, its regulation by parkin-mediated Lys(63)-linked polyubiquitination, and its dysfunction in neurodegenerative diseases.

Figure 1. The aggresome–autophagy pathway and its regulation by parkin-mediated Lys⁶³-linked polyubiquitination

Protein misfolding can occur as a result of genetic mutations or oxidative damage (1). Once formed, misfolded proteins may be refolded by chaperones (2) or tagged with Lys⁴⁸-linked polyubiquitin chains (3) for degradation by the proteasome (4). When the chaperone and proteasome systems fail or are overwhelmed, misfolded proteins form oligomers and aggregates (5) that can cause cytotoxicity. Recent evidence indicates that, under conditions of proteasomal impairment, PD-linked E3 ligase parkin co-operates with the E2 enzyme Ubc13/Uev1a to mediate Lys⁶³-linked polyubiquitination of misfolded proteins (6). The Lys⁶³-linked polyubiquitin chains promote binding to HDAC6 (7) and thereby link the misfolded proteins to the dynein motor complex for retrograde transport towards the MTOC to form the aggresome (8). Lys⁶³-linked polyubiquitination may also promote binding to p62 and thereby facilitate the recruitment of autophagic membrane to the aggresome for the formation of an autophagosome (9). Subsequent fusion of the autophagosome with the lysosome allows the degradation of misfolded and aggregated proteins by lysosomal hydrolases (10).