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

Leslie Michels Thompson, Charity T. Aiken, Linda S. Kaltenbach, Namita Agrawal, Katalin Illes, Ali Khoshnan, Marta Martinez-Vincente, Montserrat Arrasate, Jacqueline Gire O'Rourke, Hasan Khashwji, Tamas Lukacsovich, Ya Zhen Zhu, Alice L. Lau, Ashish Massey, Michael R. Hayden, Scott O. Zeitlin, Steven Finkbeiner, Kim N. Green, Frank M. LaFerla, Gillian BatesLan Huang, Paul H. Patterson, Donald C. Lo, Ana Maria Cuervo, J. Lawrence Marsh, Joan S. Steffan

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1083-1099
Number of pages17
JournalJournal of Cell Biology
Volume187
Issue number7
DOIs
StatePublished - Dec 28 2009

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ASJC Scopus subject areas

  • Cell Biology

Cite this

Thompson, L. M., Aiken, C. T., Kaltenbach, L. S., Agrawal, N., Illes, K., Khoshnan, A., Martinez-Vincente, M., Arrasate, M., O'Rourke, J. G., Khashwji, H., Lukacsovich, T., Zhu, Y. Z., Lau, A. L., Massey, A., Hayden, M. R., Zeitlin, S. O., Finkbeiner, S., Green, K. N., LaFerla, F. M., ... Steffan, J. S. (2009). IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome. Journal of Cell Biology, 187(7), 1083-1099. https://doi.org/10.1083/jcb.200909067