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

doi:10.1083/jcb.200507002

Published online 14 November 2005. doi:10.1083/jcb.200507002
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 171, Number 4, 603-614

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Article

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

Geir Bjørkøy¹, Trond Lamark¹, Andreas Brech², Heidi Outzen¹, Maria Perander¹, Aud Øvervatn¹, Harald Stenmark², and Terje Johansen¹

¹ Biochemistry Department, Institute of Medical Biology, University of Tromsø, 9037 Tromsø, Norway
² Department of Biochemistry, The Norwegian Radium Hospital, Montebello, N-0310 Oslo, Norway

Correspondence to Terje Johansen: terjej{at}fagmed.uit.no

Autophagic degradation of ubiquitinated protein aggregates isimportant for cell survival, but it is not known how the autophagicmachinery recognizes such aggregates. In this study, we reportthat polymerization of the polyubiquitin-binding protein p62/SQSTM1yields protein bodies that either reside free in the cytosoland nucleus or occur within autophagosomes and lysosomal structures.Inhibition of autophagy led to an increase in the size and numberof p62 bodies and p62 protein levels. The autophagic markerlight chain 3 (LC3) colocalized with p62 bodies and coimmunoprecipitatedwith p62, suggesting that these two proteins participate inthe same complexes. The depletion of p62 inhibited recruitmentof LC3 to autophagosomes under starvation conditions. Strikingly,p62 and LC3 formed a shell surrounding aggregates of mutanthuntingtin. Reduction of p62 protein levels or interferencewith p62 function significantly increased cell death that wasinduced by the expression of mutant huntingtin. We suggest thatp62 may, via LC3, be involved in linking polyubiquitinated proteinaggregates to the autophagy machinery.

Abbreviations used in this paper: EEA1, early endosome antigen1; LC3, light chain 3; PB1, Phox and Bem1p; siRNA, small interferingRNA; UBA; ubiquitin associated.

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