Aggresome Formation

Abstract

Bulk protein degradation in the cell is catalyzed by the ubiquitin-proteasome system (UPS). At the heart of the UPS is the proteasome, a large multisubunit tightly-regulated protease. The UPS performs key functions in protein quality control by monitoring and eliminating potentially toxic misfolded or damaged proteins. When the capacity of this protease system is exceeded, misfolded protein substrates aggregate and are assembled through an active and regulated process to form an aggresome. Aggresomes are dynamic structures, formed as a general response to an overload of improperly folded proteins. Assembly of aggresomes occurs at the centrosome, a perinuclear structure that also serves as a site for the recruitment and concentration of components of the UPS, including the proteasome, its regulators, and other proteins typically involved in protein quality control. Thus, in addition to other cellular activities, the centrosome may play a central role in protein quality control, sitting at the crossroads of protein folding, degradation, and aggregation.

Endoplasmic Reticulum Vacuolization and Valosin-Containing Protein Relocalization Result from Simultaneous Hsp90 Inhibition by Geldanamycin and Proteasome Inhibition by Velcade

“…7B; refs. 18,19,26). Longer image capture (exposure) revealed that essentially all of the VCP-GFP fusion protein had been depleted from the cytoplasm, and no residual VCP-GFP fluorescence remained on ER membranes or on drug-induced vacuoles (data not shown).…”

“…These observations prompted us to hypothesize that a buildup of misfolded, nondegradable Hsp90 client proteins might be responsible for the enhanced cytotoxicity of this drug combination (20). Both 17-AAG (5,10) and Velcade (22)(23)(24)(25) show promising clinical activity against various human cancers, and these drugs are currently in multiple advanced combinatory trials with standard first-line anticancer drugs (9,26). Recently, a phase I clinical trial of 17-AAG combined with Velcade was initiated at several cancer research centers.…”

The benefits of local depletion: The centrosome as a scaffold for ubiquitin-proteasome-mediated degradation

“…27 Aggresomes are rich in ubiquitin, 19S and 20S proteasome subunits, and the chaperones Hsp70 and Hsp90. 28 Additionally, aggresome formation triggers redistribution of vimentin intermediate filaments from cytoplasmic networks to a cage-like structure surrounding the aggresome core. 22 Thus, when the capacity of the proteasome is exceeded, as in cases where toxic proteins are overexpressed, 29 a dramatic cellular response involving cytoskeletal reorganization and trafficking events ensures that misfolded/damaged proteins are sequestered along with ubiquitin-proteasome and other quality-control components specifically at the centrosome.…”

“…28,36,37 Indeed, isolated examples of centrosomally-degraded substrates involved in a host of biological processes continue to emerge, which we discuss below (Individual examples covered in this review are shown in Fig. 1).…”

Golgi Specificity and Development of Autoreactive B Cells

“…Aggresomes, another class of intracellular protein accumulation, arise due to incomplete proteasomal degradation of misfolded proteins. Aggresome formation is microtubule dependent and occurs due to assemblage of smaller aggregates in the cell to the MTOC area (276). Both of these intracellular sequestration mechanisms retain proteins in the cell although in different locations.…”