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IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome.

Expansion of the polyglutamine repeat within the protein Huntingtin (Htt) causes Huntington's disease, a neurodegenerative disease associated with aging and the accumulation of mutant Htt in diseased neurons. Understanding the mechanisms that influence Htt cellular degradation may target treatments designed to activate mutant Htt clearance pathways. We find that Htt is phosphorylated by the inflammatory kinase IKK, enhancing its normal clearance by the proteasome and lysosome. Phosphorylation of Htt regulates additional post-translational modifications, including Htt ubiquitination, SUMOylation, and acetylation, and increases Htt nuclear localization, cleavage, and clearance mediated by lysosomal-associated membrane protein 2A and Hsc70. We propose that IKK activates mutant Htt clearance until an age-related loss of proteasome/lysosome function promotes accumulation of toxic post-translationally modified mutant Htt. Thus, IKK activation may modulate mutant Htt neurotoxicity depending on the cell's ability to degrade the modified species.

Pubmed ID: 20026656


  • Thompson LM
  • Aiken CT
  • Kaltenbach LS
  • Agrawal N
  • Illes K
  • Khoshnan A
  • Martinez-Vincente M
  • Arrasate M
  • O'Rourke JG
  • Khashwji H
  • Lukacsovich T
  • Zhu YZ
  • Lau AL
  • Massey A
  • Hayden MR
  • Zeitlin SO
  • Finkbeiner S
  • Green KN
  • LaFerla FM
  • Bates G
  • Huang L
  • Patterson PH
  • Lo DC
  • Cuervo AM
  • Marsh JL
  • Steffan JS


The Journal of cell biology

Publication Data

December 28, 2009

Associated Grants

  • Agency: NIA NIH HHS, Id: 2P01AG022074
  • Agency: NINDS NIH HHS, Id: 2R01NS039074
  • Agency: NINDS NIH HHS, Id: 2R01NS045191
  • Agency: NIGMS NIH HHS, Id: GM74830
  • Agency: NICHD NIH HHS, Id: HD36081
  • Agency: NINDS NIH HHS, Id: NS043466
  • Agency: NINDS NIH HHS, Id: NS045283
  • Agency: NINDS NIH HHS, Id: NS055298
  • Agency: NINDS NIH HHS, Id: NS52789
  • Agency: NIA NIH HHS, Id: P01AG031782
  • Agency: NIGMS NIH HHS, Id: R01 GM074830
  • Agency: NINDS NIH HHS, Id: R01 NS043466
  • Agency: NIGMS NIH HHS, Id: T32GM0731130

Mesh Terms

  • Animals
  • Brain
  • Cell Line
  • Humans
  • I-kappa B Kinase
  • Lysosomes
  • Mice
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Phosphorylation
  • Proteasome Endopeptidase Complex
  • Protein Structure, Tertiary
  • Rats
  • Rats, Sprague-Dawley
  • Solubility
  • Ubiquitination