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J. Cell Biol.,
Volume 143, Number 7, December 28, 1998 1883-1898
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.
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