Aggresome formation is a highly regulated process that possibly serves to organize misfolded proteins into a single location.
Why these aggregates form despite the existence of cellular machinery to recognize and degrade misfolded protein, and how they are delivered to cytoplasmic inclusions, are not known.
Similarly, inhibition of proteasome function also prevents the degradation of unassembled presenilin-1 (PSE1) molecules leading to their aggregation and deposition in aggresomes.
Aggresome formation is a general response of cells which occurs when the capacity of the proteasome is exceeded by the production of aggregation-prone misfolded proteins.
The formation of the aggresome is largely believed to be a protective response, sequestering potentially cytotoxic aggregates and also acting as a staging center for eventual autophagic clearance from the cell.
However, proteasome or Hsp90 inhibition rapidly triggered their translocation into the aggresome, and surprisingly, this response was independent on the expression level of synphilin 1.
Importantly, translocation to aggresomes required a special aggresome-targeting signal within the sequence of synphilin 1, an ankyrin-like repeat domain.
Furthermore, substitution of the ankyrin-like repeat in synphilin 1 with an aggresome-targeting signal from huntingtin was sufficient for aggresome formation upon inhibition of the proteasome.
Analogously, attachment of the ankyrin-like repeat to a huntingtin fragment lacking its aggresome-targeting signal promoted its transport to aggresomes.
Experiments show that mutant androgen receptor (AR), the protein responsible for X-linked spinobulbar muscular atrophy, forms insoluble aggregates and is toxic to cultured cells.
Together, these findings suggest that aggresomes are cytoprotective, serving as cytoplasmic recruitment centers to facilitate degradation of toxic proteins.
Cystic fibrosis transmembrane conductance regulator (CFTR) is an inefficiently folded integral membrane protein that is degraded by the cytoplasmic ubiquitin-proteasome pathway.
There is emerging evidence that inhibiting the aggresome pathway leads to accumulation of misfolded proteins and apoptosis in tumor cells through autophagy.