A novel GTPase, CRAG, mediates promyelocytic leukemia protein-associated nuclear body formation and degradation of expanded polyglutamine protein

J Cell Biol. 2006 Feb 13;172(4):497-504. doi: 10.1083/jcb.200505079. Epub 2006 Feb 6.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Autophagy-Related Protein 7
  • Autophagy-Related Proteins
  • Cells, Cultured
  • GTP Phosphohydrolases / genetics
  • GTP Phosphohydrolases / metabolism*
  • HeLa Cells
  • Humans
  • Intranuclear Inclusion Bodies / metabolism*
  • Mice
  • Molecular Sequence Data
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Nuclear Localization Signals / genetics
  • Nuclear Localization Signals / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Peptides / metabolism*
  • Promyelocytic Leukemia Protein
  • Rats
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Ubiquitin-Activating Enzymes / metabolism
  • Ubiquitin-Conjugating Enzymes / metabolism
  • Ultraviolet Rays

Substances

  • Autophagy-Related Proteins
  • Neoplasm Proteins
  • Nuclear Localization Signals
  • Nuclear Proteins
  • Peptides
  • Pml protein, mouse
  • Promyelocytic Leukemia Protein
  • Transcription Factors
  • Tumor Suppressor Proteins
  • PML protein, human
  • polyglutamine
  • Ubiquitin-Conjugating Enzymes
  • GTP Phosphohydrolases
  • ATG7 protein, human
  • Autophagy-Related Protein 7
  • Ubiquitin-Activating Enzymes
  • ATG3 protein, human

Associated data

  • GENBANK/AB078345