Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / chemistry
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Aging / metabolism
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Aging / pathology
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Animals
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Autophagy / genetics
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Brain / cytology
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Brain / metabolism*
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DNA-Binding Proteins
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Drosophila Proteins / chemistry
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Drosophila Proteins / genetics
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Drosophila Proteins / metabolism*
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Drosophila melanogaster / cytology
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Drosophila melanogaster / metabolism*
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Humans
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Inclusion Bodies / genetics
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Inclusion Bodies / metabolism*
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Mutation / genetics
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Nerve Tissue Proteins / metabolism*
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Neurodegenerative Diseases / genetics
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Neurodegenerative Diseases / metabolism
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Neurodegenerative Diseases / physiopathology
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Nuclear Proteins / chemistry
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Proteasome Endopeptidase Complex / genetics
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Proteasome Endopeptidase Complex / metabolism
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Protein Structure, Tertiary / genetics
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Sequestosome-1 Protein
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Ubiquitin / genetics
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Ubiquitin / metabolism
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Ubiquitination / genetics
Substances
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Adaptor Proteins, Signal Transducing
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DNA-Binding Proteins
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Drosophila Proteins
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Nerve Tissue Proteins
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Nuclear Proteins
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SQSTM1 protein, human
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Sequestosome-1 Protein
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Ubiquitin
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ref(2)P protein, Drosophila
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Proteasome Endopeptidase Complex