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 Bates; Lan Huang; Paul H. Patterson; Donald C. Lo; Ana Maria Cuervo; J. Lawrence Marsh; Joan S. Steffan

doi:10.1083/jcb.200909067

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

Medical & Molecular Genetics

Research output: Contribution to journal › Article › peer-review

314 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 language	English
Pages (from-to)	1083 - 1099
Number of pages	17
Journal	Journal of Cell Biology
Volume	187
Issue number	7
DOIs	https://doi.org/10.1083/jcb.200909067
Publication status	Published - 28 Dec 2009

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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

@article{6d98e104f44d44ab889cfb647c588485,

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 Ya-Zhen Zhu 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 = dec,

day = "28",

doi = "10.1083/jcb.200909067",

language = "English",

volume = "187",

pages = "1083 -- 1099",

journal = "Journal of Cell Biology",

publisher = "Rockefeller University Press",

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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 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

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.

U2 - 10.1083/jcb.200909067

DO - 10.1083/jcb.200909067

M3 - Article

VL - 187

SP - 1083

EP - 1099

JO - Journal of Cell Biology

JF - Journal of Cell Biology

IS - 7

ER -

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

Abstract

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