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

Research output: Contribution to journalArticle

228 Citations (Scopus)

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

Fingerprint

Proteasome Endopeptidase Complex
Lysosomes
Lysosome-Associated Membrane Glycoproteins
Sumoylation
Aptitude
Poisons
Ubiquitination
Huntington Disease
Post Translational Protein Processing
Acetylation
Neurodegenerative Diseases
Phosphotransferases
Phosphorylation
Neurons
polyglutamine
Huntingtin Protein

ASJC Scopus subject areas

  • Cell Biology

Cite this

Thompson, L. M., Aiken, C. T., Kaltenbach, L. S., Agrawal, N., Illes, K., Khoshnan, A., ... 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

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

In: Journal of Cell Biology, Vol. 187, No. 7, 28.12.2009, p. 1083-1099.

Research output: Contribution to journalArticle

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 2009, 'IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome', Journal of Cell Biology, vol. 187, no. 7, pp. 1083-1099. https://doi.org/10.1083/jcb.200909067
Thompson LM, Aiken CT, Kaltenbach LS, Agrawal N, Illes K, Khoshnan A et al. IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome. Journal of Cell Biology. 2009 Dec 28;187(7):1083-1099. https://doi.org/10.1083/jcb.200909067
Thompson, Leslie Michels ; Aiken, Charity T. ; Kaltenbach, Linda S. ; Agrawal, Namita ; Illes, Katalin ; Khoshnan, Ali ; Martinez-Vincente, Marta ; Arrasate, Montserrat ; O'Rourke, Jacqueline Gire ; Khashwji, Hasan ; Lukacsovich, Tamas ; Zhu, Ya Zhen ; Lau, Alice L. ; Massey, Ashish ; Hayden, Michael R. ; Zeitlin, Scott O. ; Finkbeiner, Steven ; Green, Kim N. ; LaFerla, Frank M. ; Bates, Gillian ; Huang, Lan ; Patterson, Paul H. ; Lo, Donald C. ; Cuervo, Ana Maria ; Marsh, J. Lawrence ; Steffan, Joan S. / IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome. In: Journal of Cell Biology. 2009 ; Vol. 187, No. 7. pp. 1083-1099.
@article{3944e788969a48ed99d0a6cdcd80c9c2,
title = "IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome",
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.",
author = "Thompson, {Leslie Michels} and Aiken, {Charity T.} and Kaltenbach, {Linda S.} and Namita Agrawal and Katalin Illes and Ali Khoshnan and Marta Martinez-Vincente and Montserrat Arrasate and O'Rourke, {Jacqueline Gire} and Hasan Khashwji and Tamas Lukacsovich and Zhu, {Ya Zhen} and Lau, {Alice L.} and Ashish Massey and Hayden, {Michael R.} and Zeitlin, {Scott O.} and Steven Finkbeiner and Green, {Kim N.} and LaFerla, {Frank M.} and Gillian Bates and Lan Huang and Patterson, {Paul H.} and Lo, {Donald C.} and Cuervo, {Ana Maria} and Marsh, {J. Lawrence} and Steffan, {Joan S.}",
year = "2009",
month = "12",
day = "28",
doi = "10.1083/jcb.200909067",
language = "English (US)",
volume = "187",
pages = "1083--1099",
journal = "Journal of Cell Biology",
issn = "0021-9525",
publisher = "Rockefeller University Press",
number = "7",

}

TY - JOUR

T1 - IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome

AU - Thompson, Leslie Michels

AU - Aiken, Charity T.

AU - Kaltenbach, Linda S.

AU - Agrawal, Namita

AU - Illes, Katalin

AU - Khoshnan, Ali

AU - Martinez-Vincente, Marta

AU - Arrasate, Montserrat

AU - O'Rourke, Jacqueline Gire

AU - Khashwji, Hasan

AU - Lukacsovich, Tamas

AU - Zhu, Ya Zhen

AU - Lau, Alice L.

AU - Massey, Ashish

AU - Hayden, Michael R.

AU - Zeitlin, Scott O.

AU - Finkbeiner, Steven

AU - Green, Kim N.

AU - LaFerla, Frank M.

AU - Bates, Gillian

AU - Huang, Lan

AU - Patterson, Paul H.

AU - Lo, Donald C.

AU - Cuervo, Ana Maria

AU - Marsh, J. Lawrence

AU - Steffan, Joan S.

PY - 2009/12/28

Y1 - 2009/12/28

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=72149124383&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=72149124383&partnerID=8YFLogxK

U2 - 10.1083/jcb.200909067

DO - 10.1083/jcb.200909067

M3 - Article

C2 - 20026656

AN - SCOPUS:72149124383

VL - 187

SP - 1083

EP - 1099

JO - Journal of Cell Biology

JF - Journal of Cell Biology

SN - 0021-9525

IS - 7

ER -