Abstract
Polyglutamine diseases are inherited neurodegenerative diseases caused by the expanded polyglutamine proteins (polyQs). We have identified a novel guanosine triphosphatase (GTPase) named CRAG that contains a nuclear localization signal (NLS) sequence and forms nuclear inclusions in response to stress. After ultraviolet irradiation, CRAG interacted with and induced an enlarged ring-like structure of promyelocytic leukemia protein (PML) body in a GTPase-dependent manner. Reactive oxygen species (ROS) generated by polyQ accumulation triggered the association of CRAG with polyQ and the nuclear translocation of the CRAG-polyQ complex. Furthermore, CRAG promoted the degradation of polyQ at PML/CRAG bodies through the ubiquitin-proteasome pathway. CRAG knockdown by small interfering RNA in neuronal cells consistently blocked the nuclear translocation of polyQ and enhanced polyQ-mediated cell death. We propose that CRAG is a modulator of PML function and dynamics in ROS signaling and is protectively involved in the pathogenesis of polyglutamine diseases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Autophagy-Related Protein 7
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Autophagy-Related Proteins
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Cells, Cultured
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GTP Phosphohydrolases / genetics
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GTP Phosphohydrolases / metabolism*
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HeLa Cells
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Humans
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Intranuclear Inclusion Bodies / metabolism*
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Mice
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Molecular Sequence Data
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Nuclear Localization Signals / genetics
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Nuclear Localization Signals / metabolism
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Peptides / metabolism*
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Promyelocytic Leukemia Protein
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Rats
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
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Ubiquitin-Activating Enzymes / metabolism
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Ubiquitin-Conjugating Enzymes / metabolism
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Ultraviolet Rays
Substances
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Autophagy-Related Proteins
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Neoplasm Proteins
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Nuclear Localization Signals
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Nuclear Proteins
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Peptides
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Pml protein, mouse
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Promyelocytic Leukemia Protein
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Transcription Factors
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Tumor Suppressor Proteins
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PML protein, human
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polyglutamine
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Ubiquitin-Conjugating Enzymes
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GTP Phosphohydrolases
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ATG7 protein, human
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Autophagy-Related Protein 7
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Ubiquitin-Activating Enzymes
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ATG3 protein, human