Aggrephagy: Selective Disposal of Protein Aggregates by Macroautophagy

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.