Aggrephagy: Selective Disposal of Protein Aggregates by Macroautophagy

Figure 1

Proteins recognized as misfolded by molecular chaperones can be degraded by selective autophagy, the ubiquitin-proteasome system (UPS) or chaperone-mediated autophagy (CMA). In selective autophagy, misfolded proteins are often assembled into aggregates before they are degraded. They are also often ubiquitinated, and this induces the recruitment of ubiquitin binding cargo receptors such as p62 and NBR1. These cargo receptors bind to ubiquitinated cargos (in this case a protein aggregate) and to ATG8 homologues conjugated to the inner surface of the phagophore (LC3 indicated as blue dots). This way, cargos are selectively delivered to the inner surface of the phagophore. An autophagosome is formed by closure of the phagophore. The autophagosome fuses with a late endosome or with a lysosome, but the end point is in both cases the formation of an autolysosome where the contents are degraded. Substrates for the UPS and CMA degradation pathways need to be in a soluble and monomeric form. Degradation by the UPS depends on K48-linked polyubiquitination of the misfolded substrate. The substrate is then delivered to the 26S proteasome, where it is deubiquitinated and degraded. Degradation by CMA depends on an Hsc70-mediated recognition of a KFERQ motif on the misfolded substrate. The substrate is then delivered to the lysosomal receptor LAMP-2A, transported into the lumen of the lysosome, and degraded.