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Published online March 17, 2008
doi:10.1083/jcb.200711108
The Journal of Cell Biology, Vol. 180, No. 6, 1065-1071
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Nezis et al.
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 Ref(2)P, the Drosophila melanogaster homologue of mammalian p62, is required for the formation of protein aggregates in adult brain

Ioannis P. Nezis1, Anne Simonsen1, Antonia P. Sagona1, Kim Finley2, Sébastien Gaumer3,4, Didier Contamine3,4, Tor Erik Rusten1, Harald Stenmark1, and Andreas Brech1

1 Department of Biochemistry, Centre for Cancer Biomedicine, University of Oslo and Institute for Cancer Research, The Norwegian Radium Hospital, N-0310 Oslo, Norway
2 Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037
3 Université Versailles St-Quentin, Laboratoire de Génétique et de Biologie Cellulaire, Versailles Cedex 78035, France
4 Centre National de la Recherche Scientifique, Unité Mixte de Reserche 8159, Laboratoire de Génétique et de Biologie Cellulaire, Versailles Cedex 78035, France

Correspondence to Harald Stenmark: stenmark{at}ulrik.uio.no; or Andreas Brech: Andreas.Brech{at}rr-research.no

p62 has been proposed to mark ubiquitinated protein bodies for autophagic degradation. We report that the Drosophila melanogaster p62 orthologue, Ref(2)P, is a regulator of protein aggregation in the adult brain. We demonstrate that Ref(2)P localizes to age-induced protein aggregates as well as to aggregates caused by reduced autophagic or proteasomal activity. A similar localization to protein aggregates is also observed in D. melanogaster models of human neurodegenerative diseases. Although atg8a autophagy mutant flies show accumulation of ubiquitin- and Ref(2)P-positive protein aggregates, this is abrogated in atg8a/ref(2)P double mutants. Both the multimerization and ubiquitin binding domains of Ref(2)P are required for aggregate formation in vivo. Our findings reveal a major role for Ref(2)P in the formation of ubiquitin-positive protein aggregates both under physiological conditions and when normal protein turnover is inhibited.

Abbreviations used in this paper: PB1, Phox and Bem1p; UAS, upstream activator sequence; UBA, ubiquitin-associated.


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