Aggrephagy: Selective Disposal of Protein Aggregates by Macroautophagy

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.