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p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell

Geir Bjørkøy1, Trond Lamark, Andreas Brech

  • 1Biochemistry Department, Institute of Medical Biology, University of Tromsø, 9037 Tromsø, Norway.

The Journal of Cell Biology
|November 16, 2005
PubMed

Insights

The protein p62/SQSTM1 forms bodies that bind to ubiquitinated protein aggregates. P62 links these aggregates to the autophagy machinery via LC3, aiding cell survival.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Autophagic degradation removes ubiquitinated protein aggregates, crucial for cell survival.
  • The mechanism by which autophagy recognizes these aggregates remains unclear.

Purpose of the Study:

  • To investigate the role of p62/SQSTM1 in recognizing and targeting ubiquitinated protein aggregates for autophagic degradation.
  • To elucidate the interaction between p62/SQSTM1, LC3, and protein aggregates.

Main Methods:

  • Observation of p62/SQSTM1 polymerization into protein bodies.
  • Inhibition of autophagy and assessment of p62 body dynamics.
  • Co-immunoprecipitation and colocalization studies of p62 and LC3.
  • Analysis of cell death in response to mutant huntingtin expression with altered p62 levels.

Main Results:

  • p62/SQSTM1 polymerizes into bodies found in cytosol, nucleus, and autophagosomes.
  • Autophagy inhibition increased p62 body size and levels.
  • p62 colocalized and co-immunoprecipitated with the autophagic marker LC3.
  • p62 depletion impaired LC3 recruitment to autophagosomes.
  • p62 and LC3 formed a shell around mutant huntingtin aggregates.
  • Reduced p62 levels or function increased cell death induced by mutant huntingtin.

Conclusions:

  • p62/SQSTM1 plays a critical role in linking polyubiquitinated protein aggregates to the autophagy machinery.
  • The p62-LC3 interaction is essential for the autophagic clearance of toxic protein aggregates.
  • p62 facilitates cell survival by promoting the degradation of mutant huntingtin.

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