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© The Rockefeller University Press, 0021-9525/1998//1883 $5.00
The Journal of Cell Biology, Volume 143, Number 7, , 1998 1883-1898

Regular Articles

Aggresomes: A Cellular Response to Misfolded Proteins



Jennifer A. Johnston, Cristina L. Ward, and Ron R. Kopito

Department of Biological Sciences, Stanford University, Stanford, California 94305-5020

Intracellular deposition of misfolded protein aggregates into ubiquitin-rich cytoplasmic inclusions is linked to the pathogenesis of many diseases. 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. We have investigated the intracellular fate of cystic fibrosis transmembrane conductance regulator (CFTR), an inefficiently folded integral membrane protein which is degraded by the cytoplasmic ubiquitin-proteasome pathway. Overexpression or inhibition of proteasome activity in transfected human embryonic kidney or Chinese hamster ovary cells led to the accumulation of stable, high molecular weight, detergent-insoluble, multiubiquitinated forms of CFTR. Using immunofluorescence and transmission electron microscopy with immunogold labeling, we demonstrate that undegraded CFTR molecules accumulate at a distinct pericentriolar structure which we have termed the aggresome. Aggresome formation is accompanied by redistribution of the intermediate filament protein vimentin to form a cage surrounding a pericentriolar core of aggregated, ubiquitinated protein. Disruption of microtubules blocks the formation of aggresomes. Similarly, inhibition of proteasome function also prevented the degradation of unassembled presenilin-1 molecules leading to their aggregation and deposition in aggresomes. These data lead us to propose that 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.

Key Words: ubiquitin • proteasome • intermediate filaments • protein aggregation • presenilin

Abbreviations used in this paper: ALLN, acetyl-leucyl-leucyl-norleucinal; CFTR, cystic fibrosis transmembrane conductance regulator; HEK, human embryonic kidney 293; IF, intermediate filaments; LAMP, lysosomal membrane protein; manII, {alpha}-mannosidase II; MT, microtubules; MTOC, microtubule-organizing center; PS, presenilin.


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