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. 2012:2012:736905.
doi: 10.1155/2012/736905. Epub 2012 Mar 22.

Aggrephagy: selective disposal of protein aggregates by macroautophagy

Trond Lamark  1 , Terje Johansen
Affiliations

Aggrephagy: selective disposal of protein aggregates by macroautophagy

Trond Lamark et al. Int J Cell Biol. 2012.

Abstract

Protein aggregation is a continuous process in our cells. Some proteins aggregate in a regulated manner required for different vital functional processes in the cells whereas other protein aggregates result from misfolding caused by various stressors. The decision to form an aggregate is largely made by chaperones and chaperone-assisted proteins. Proteins that are damaged beyond repair are degraded either by the proteasome or by the lysosome via autophagy. The aggregates can be degraded by the proteasome and by chaperone-mediated autophagy only after dissolution into soluble single peptide species. Hence, protein aggregates as such are degraded by macroautophagy. The selective degradation of protein aggregates by macroautophagy is called aggrephagy. Here we review the processes of aggregate formation, recognition, transport, and sequestration into autophagosomes by autophagy receptors and the role of aggrephagy in different protein aggregation diseases.

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Figures

Figure 1
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.
Figure 2
Figure 2
Protein degradation assisted by heat shock proteins and their co-chaperones. (a) Substrates selected for degradation by heat shock proteins are either defective ribosomal products (DRiPs) or Hsp90 client proteins that start to unfold or aggregate. Formation of the latter type of substrate is increased under conditions of oxidative stress or during aging. (b) Misfolded and monomeric substrates bound to Hsp70/Hsc70 are preferentially degraded by CMA or by the UPS. (c) In response to aggregation, or if the capacity of CMA and the UPS is insufficient, substrates are degraded by chaperone-assisted selective autophagy (CASA). This process relies on the co-chaperones BAG3 and HspB8, the E3 ubiquitin ligase CHIP, and autophagy receptors such as p62. The process may also rely on the assembly of the misfolded substrates into p62 bodies. (d) If degradation of misfolded substrates is impaired, BAG3 interacts with dynein and transport protein aggregates along microtubules to the aggresome. The contents of aggresomes may subsequently be degraded by aggrephagy.
Figure 3
Figure 3
Protein degradation assisted by p97/VCP and HDAC6. (a) Misfolded substrates located in the ER lumen or at the ER membrane are recognized by the ER luminal Hsp70 homologue BiP/Grp78 and degraded by ER-associated degradation (ERAD). A complex of p97/VCP and Derlin-1 mediates the transport of ERAD substrates into the cytoplasm where they are ubiquitinated by E3 ligases such as Hrd1 and gp78 and degraded by the UPS. (b) p97/VCP mediates the segregation of ubiquitinated mitochondrial outer membrane (MOM) substrates into the cytoplasm, where they are degraded by the UPS. (c) p97/VCP mediates the segregation of selected substrates from nuclear or cytoplasmic protein complexes, followed by their degradation by the UPS. (d) p97/VCP is also required for the transport of protein aggregates to the aggresome. This depends on ubiquitination of the aggregate by an E3 ligase such as Parkin, and the delivery of the ubiquitinated aggregate to HDAC6. HDAC6 binds to K63-linked polyubiquitin chains and to dynein, and it is responsible for the transport of ubiquitinated protein aggregates along microtubules to the aggresome. The contents of aggresomes may subsequently be degraded by aggrephagy.
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