Thompson, Leslie Michels and Aiken, Charity T. and Kaltenbach, Linda S. and Agrawal, Namita and Illes, Katalin and Khoshnan, Ali and Martinez-Vicente, Marta and Arrasate, Montserrat and O'Rourke, Jacqueline Gire and Khashwji, Hasan and Lukacsovich, Tamas and Zhu, Ya-Zhen and Lau, Alice L. and Massey, Ashish and Hayden, Michael R. and Zeitlin, Scott O. and Finkbeiner, Steven and Green, Kim N. and LaFerla, Frank M. and Bates, Gillian and Huang, Lan and Patterson, Paul H. and Lo, Donald C. and Cuervo, Ana Maria and Marsh, J. Lawrence and Steffan, Joan S. (2009) IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome. Journal of Cell Biology, 187 (7). pp. 1083-1099. ISSN 0021-9525 http://resolver.caltech.edu/CaltechAUTHORS:20100125-115224074
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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.
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| Additional Information: | © 2009 Thompson et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). Submitted: 10 September 2009; accepted: 20 November 2009. This paper is dedicated to the memory of Dr. Charles H. Sawyer, whose example was its constant inspiration. We thank Drs. David Housman, Matthew Blurton-Jones, Masashi Kitazawa, Peter Kaiser, Alex Osmand, Christian Landes, Bin Liu, and Daniel Keys for insightful discussion; Denise Dunn and Emily Mitchell for technical assistance; and Anne Dejean, Dirk Bohmann, Paul Muchowski, Harm Kampinga, Peter Kaiser, Christian Tagwerker, Cam Patterson, Heidi Rommelaere, Alex Kazantsev, Robert Friedlander, Erich Wanker, and Marian DiFiglia for their generous gifts of reagents for these experiments. This work was supported by the Hereditary Disease Foundation (J.S. Steffan, L.M. Thompson, J.L. Marsh, D.C. Lo, and P.H. Patterson); the Fox Family Foundation (J.S. Steffan and L.M. Thompson); the High Q Foundation (J.S. Steffan, L.M. Thompson, J.L. Marsh, and D.C. Lo); the Huntington’s Disease Society of America Coalition for the Cure (L.M. Thompson); the Taube-Koret Center for Huntington’s Disease Research (S. Finkbeiner); and National Institutes of Health awards NS52789 (L.M. Thompson and J.L. Marsh), HD36081 (J.L. Marsh), NS045283 (J.L. Marsh and L.M. Thompson), NS043466 (S.O. Zeitlin), GM74830 (L. Huang), 2R01NS039074 (S. Finkbeiner), 2R01NS045191 (S. Finkbeiner), 2P01AG022074 (S. Finkbeiner), P01AG031782 (A.M. Cuervo) and NS055298 (P.H. Patterson), and T32GM0731130 (C.T. Aiken). | ||||||||||||||||||||||||||||||||||
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| Subject Keywords: | CMA, chaperone-mediated autophagy; HD, Huntington's disease; Htt, Huntingtin; LAMP-2A, lysosomal-associated membrane protein 2A; polyQ, polyglutamine; wt, wild type | ||||||||||||||||||||||||||||||||||
| Record Number: | CaltechAUTHORS:20100125-115224074 | ||||||||||||||||||||||||||||||||||
| Persistent URL: | http://resolver.caltech.edu/CaltechAUTHORS:20100125-115224074 | ||||||||||||||||||||||||||||||||||
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| Official Citation: | 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 Bates, Lan Huang, Paul H. Patterson, Donald C. Lo, Ana Maria Cuervo, J. Lawrence Marsh, and Joan S. Steffan IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome J. Cell Biol., Dec 2009; 187: 1083 - 1099. | ||||||||||||||||||||||||||||||||||
| Usage Policy: | No commercial reproduction, distribution, display or performance rights in this work are provided. | ||||||||||||||||||||||||||||||||||
| ID Code: | 17302 | ||||||||||||||||||||||||||||||||||
| Collection: | CaltechAUTHORS | ||||||||||||||||||||||||||||||||||
| Deposited By: | Jason Perez | ||||||||||||||||||||||||||||||||||
| Deposited On: | 29 Jan 2010 18:09 | ||||||||||||||||||||||||||||||||||
| Last Modified: | 26 Dec 2012 11:43 |
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