The paper investigates the intracellular fate of misfolded proteins, specifically cystic fibrosis transmembrane conductance regulator (CFTR) and presenilin-1 (PS1), which are inefficiently folded integral membrane proteins. Overexpression or inhibition of proteasome activity in transfected human embryonic kidney or Chinese hamster ovary cells leads to the accumulation of stable, high molecular weight, detergent-insoluble, multiubiquitinated forms of CFTR. Using immunofluorescence and transmission electron microscopy, the authors demonstrate that undegraded CFTR molecules accumulate at a distinct pericentriolar structure termed the aggresome. Aggresome formation is accompanied by the redistribution of the intermediate filament protein vimentin to form a cage surrounding a pericentriolar core of aggregated, ubiquitinated protein. Disruption of microtubules blocks aggresome formation, and inhibition of proteasome function prevents the degradation of unassembled presenilin-1 molecules, leading to their aggregation and deposition in aggresomes. These findings suggest that aggresome formation is a general cellular response to the presence of aggregated, undegraded protein when the capacity of the proteasome is exceeded by the production of aggregation-prone misfolded proteins.The paper investigates the intracellular fate of misfolded proteins, specifically cystic fibrosis transmembrane conductance regulator (CFTR) and presenilin-1 (PS1), which are inefficiently folded integral membrane proteins. Overexpression or inhibition of proteasome activity in transfected human embryonic kidney or Chinese hamster ovary cells leads to the accumulation of stable, high molecular weight, detergent-insoluble, multiubiquitinated forms of CFTR. Using immunofluorescence and transmission electron microscopy, the authors demonstrate that undegraded CFTR molecules accumulate at a distinct pericentriolar structure termed the aggresome. Aggresome formation is accompanied by the redistribution of the intermediate filament protein vimentin to form a cage surrounding a pericentriolar core of aggregated, ubiquitinated protein. Disruption of microtubules blocks aggresome formation, and inhibition of proteasome function prevents the degradation of unassembled presenilin-1 molecules, leading to their aggregation and deposition in aggresomes. These findings suggest that aggresome formation is a general cellular response to the presence of aggregated, undegraded protein when the capacity of the proteasome is exceeded by the production of aggregation-prone misfolded proteins.