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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • 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, Y-Z; 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

Published Date

  • December 21, 2009

Published In

Volume / Issue

  • 187 / 7

Start / End Page

  • 1083 - 1099

PubMed ID

  • 20026656

Pubmed Central ID

  • 20026656

Electronic International Standard Serial Number (EISSN)

  • 1540-8140

International Standard Serial Number (ISSN)

  • 0021-9525

Digital Object Identifier (DOI)

  • 10.1083/jcb.200909067

Language

  • eng