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Related Experiment Videos

Aggresomes: a cellular response to misfolded proteins

J A Johnston1, C L Ward, R R Kopito

  • 1Department of Biological Sciences, Stanford University, Stanford, California 94305-5020, USA.

The Journal of Cell Biology
|December 29, 1998
PubMed
Summary

Misfolded proteins form aggresomes, cellular structures for protein aggregates, when proteasome degradation capacity is overwhelmed. This process involves intermediate filaments and microtubules.

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Area of Science:

  • Cell Biology
  • Molecular Biology
  • Pathology

Background:

  • Misfolded protein aggregates in ubiquitin-rich inclusions are implicated in disease pathogenesis.
  • The mechanisms of aggregate formation and delivery to inclusions remain unclear.
  • The ubiquitin-proteasome pathway degrades misfolded proteins, but its capacity can be exceeded.

Purpose of the Study:

  • To investigate the intracellular fate of misfolded proteins, specifically cystic fibrosis transmembrane conductance regulator (CFTR).
  • To elucidate the cellular mechanisms involved in the formation of protein aggregate inclusions.
  • To determine if aggresome formation is a general cellular response to proteasome overload.

Main Methods:

  • Overexpression and proteasome inhibition in human embryonic kidney and Chinese hamster ovary cells.
  • Immunofluorescence and transmission electron microscopy with immunogold labeling.
  • Investigation of the role of microtubules and intermediate filaments in aggregate formation.

Main Results:

  • Misfolded CFTR accumulates as stable, high molecular weight, multiubiquitinated forms when proteasome activity is inhibited.
  • Accumulated CFTR localizes to a pericentriolar structure termed the aggresome.
  • Aggresome formation involves vimentin redistribution and requires intact microtubules.
  • Inhibition of proteasome function also leads to aggresome formation with presenilin-1.

Conclusions:

  • Aggresome formation is a cellular response to the accumulation of aggregation-prone misfolded proteins when proteasome capacity is exceeded.
  • This process involves the formation of distinct pericentriolar structures and the reorganization of the cytoskeleton.
  • The findings suggest aggresome formation is a general mechanism for dealing with proteotoxic stress.

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