IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome
Creators
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Thompson, Leslie Michels1
- Aiken, Charity T.1
- Kaltenbach, Linda S.2
- Agrawal, Namita1
- Illes, Katalin1
- Khoshnan, Ali3
- Martinez-Vicente, Marta4, 5
- Arrasate, Montserrat6
- Gire O'Rourke, Jacqueline1
- Khashwji, Hasan1
- Lukacsovich, Tamas1
- Zhu, Ya-Zhen1
- Lau, Alice L.1
- Massey, Ashish4
- Hayden, Michael R.7
- Zeitlin, Scott O.8
- Finkbeiner, Steven9, 10
- Green, Kim N.1
- LaFerla, Frank M.1
- Bates, Gillian11
- Huang, Lan1
- Patterson, Paul H.3
- Lo, Donald C.2
- Cuervo, Ana Maria4
- Marsh, J. Lawrence1
- Steffan, Joan S.1
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1.
University of California, Irvine
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2.
Duke University
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3.
California Institute of Technology
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4.
Albert Einstein College of Medicine
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5.
Bellvitge University Hospital
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6.
University of Navarra
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7.
University of British Columbia
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8.
University of Virginia
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9.
Gladstone Institutes
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10.
University of California, San Francisco
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11.
King's College London
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.
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).Attached Files
Published - Thompson2009p6701J_Cell_Biol.pdf
Supplemental Material - 1.pdf
Files
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Additional details
Identifiers
- PMCID
- PMC2806289
- Eprint ID
- 17302
- Resolver ID
- CaltechAUTHORS:20100125-115224074
Funding
- Hereditary Disease Foundation
- Fox Family Foundation
- High Q Foundation
- Huntington's Disease Society of America Coalition for the Cure
- Taube-Koret Center for Huntington's Disease Research
- NIH
- NS52789
- NIH
- HD36081
- NIH
- NS045283
- NIH
- NS043466
- NIH
- GM74830
- NIH
- 2R01NS039074
- NIH
- 2R01NS045191
- NIH
- 2P01AG022074
- NIH
- P01AG031782
- NIH
- NS055298
- NIH
- T32GM0731130
Dates
- Created
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2010-01-29Created from EPrint's datestamp field
- Updated
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2021-11-08Created from EPrint's last_modified field