Acetylation Targets Mutant Huntingtin to Autophagosomes for Degradation

Hyunkyung Jeong; Florian Then; Thomas J. Melia; Joseph R. Mazzulli; Libin Cui; Jeffrey N. Savas; Cindy Voisine; Paolo Paganetti; Naoko Tanese; Anne C. Hart; Ai Yamamoto; Dimitri Krainc

doi:10.1016/j.cell.2009.03.018

Acetylation Targets Mutant Huntingtin to Autophagosomes for Degradation

Hyunkyung Jeong, Florian Then, Thomas J. Melia, Joseph R. Mazzulli, Libin Cui, Jeffrey N. Savas, Cindy Voisine, Paolo Paganetti, Naoko Tanese, Anne C. Hart, Ai Yamamoto, Dimitri Krainc^*

^*Corresponding author for this work

Neurology

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

340 Scopus citations

Abstract

Huntington's disease (HD) is an incurable neurodegenerative disease caused by neuronal accumulation of the mutant protein huntingtin. Improving clearance of the mutant protein is expected to prevent cellular dysfunction and neurodegeneration in HD. We report here that such clearance can be achieved by posttranslational modification of the mutant Huntingtin (Htt) by acetylation at lysine residue 444 (K444). Increased acetylation at K444 facilitates trafficking of mutant Htt into autophagosomes, significantly improves clearance of the mutant protein by macroautophagy, and reverses the toxic effects of mutant huntingtin in primary striatal and cortical neurons and in a transgenic C. elegans model of HD. In contrast, mutant Htt that is rendered resistant to acetylation dramatically accumulates and leads to neurodegeneration in cultured neurons and in mouse brain. These studies identify acetylation as a mechanism for removing accumulated protein in HD, and more broadly for actively targeting proteins for degradation by autophagy.

Original language	English (US)
Pages (from-to)	60-72
Number of pages	13
Journal	Cell
Volume	137
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2009.03.018
State	Published - Apr 3 2009

Funding

We are grateful to Drs. K. Kegel, M. DiFiglia, C.D. Allis, A. Basu, H. Park, and A.B. Young and members of the Krainc laboratory for helpful suggestions and comments on the manuscript. We also thank Drs. D. Sarracino, B. Krastins, J. Kowalak, S. Markey, and A. Makusky for help with mass spectrometry; B. Hyman, W. Stoothoff, and C. Lill for help with live-cell imaging; E. Regulier for help with lentiviral transductions; A. Weiss and A. Roscic for help with HN10 cells; H. Ischiropoulos for use of HPLC system; N. Mizushima for Atg5-deficient cells; A. Kazantsev for CBP and CBPΔQ constructs; Y. Yoshimori for GFP-LC3; G.A. Fitzgerald for p300 and P/CAF; P.W. Faber for osm::Htt564-150Q ; and the New York Structural Biology Center for the EM facilities. This work was supported by R01NS050352 and R01 NS051303 (to D.K.) and R01 NS050199 (to A.Y.). F.T. is a fellow of the DFG. Author contributions: H.J. and F.T. contributed equally to this work.

Keywords

MOLNEURO

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2009.03.018

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title = "Acetylation Targets Mutant Huntingtin to Autophagosomes for Degradation",

abstract = "Huntington's disease (HD) is an incurable neurodegenerative disease caused by neuronal accumulation of the mutant protein huntingtin. Improving clearance of the mutant protein is expected to prevent cellular dysfunction and neurodegeneration in HD. We report here that such clearance can be achieved by posttranslational modification of the mutant Huntingtin (Htt) by acetylation at lysine residue 444 (K444). Increased acetylation at K444 facilitates trafficking of mutant Htt into autophagosomes, significantly improves clearance of the mutant protein by macroautophagy, and reverses the toxic effects of mutant huntingtin in primary striatal and cortical neurons and in a transgenic C. elegans model of HD. In contrast, mutant Htt that is rendered resistant to acetylation dramatically accumulates and leads to neurodegeneration in cultured neurons and in mouse brain. These studies identify acetylation as a mechanism for removing accumulated protein in HD, and more broadly for actively targeting proteins for degradation by autophagy.",

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author = "Hyunkyung Jeong and Florian Then and Melia, {Thomas J.} and Mazzulli, {Joseph R.} and Libin Cui and Savas, {Jeffrey N.} and Cindy Voisine and Paolo Paganetti and Naoko Tanese and Hart, {Anne C.} and Ai Yamamoto and Dimitri Krainc",

note = "Funding Information: We are grateful to Drs. K. Kegel, M. DiFiglia, C.D. Allis, A. Basu, H. Park, and A.B. Young and members of the Krainc laboratory for helpful suggestions and comments on the manuscript. We also thank Drs. D. Sarracino, B. Krastins, J. Kowalak, S. Markey, and A. Makusky for help with mass spectrometry; B. Hyman, W. Stoothoff, and C. Lill for help with live-cell imaging; E. Regulier for help with lentiviral transductions; A. Weiss and A. Roscic for help with HN10 cells; H. Ischiropoulos for use of HPLC system; N. Mizushima for Atg5-deficient cells; A. Kazantsev for CBP and CBPΔQ constructs; Y. Yoshimori for GFP-LC3; G.A. Fitzgerald for p300 and P/CAF; P.W. Faber for osm::Htt564-150Q ; and the New York Structural Biology Center for the EM facilities. This work was supported by R01NS050352 and R01 NS051303 (to D.K.) and R01 NS050199 (to A.Y.). F.T. is a fellow of the DFG. Author contributions: H.J. and F.T. contributed equally to this work. ",

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AU - Jeong, Hyunkyung

AU - Then, Florian

AU - Melia, Thomas J.

AU - Mazzulli, Joseph R.

AU - Cui, Libin

AU - Savas, Jeffrey N.

AU - Voisine, Cindy

AU - Paganetti, Paolo

AU - Tanese, Naoko

AU - Hart, Anne C.

AU - Yamamoto, Ai

AU - Krainc, Dimitri

N1 - Funding Information: We are grateful to Drs. K. Kegel, M. DiFiglia, C.D. Allis, A. Basu, H. Park, and A.B. Young and members of the Krainc laboratory for helpful suggestions and comments on the manuscript. We also thank Drs. D. Sarracino, B. Krastins, J. Kowalak, S. Markey, and A. Makusky for help with mass spectrometry; B. Hyman, W. Stoothoff, and C. Lill for help with live-cell imaging; E. Regulier for help with lentiviral transductions; A. Weiss and A. Roscic for help with HN10 cells; H. Ischiropoulos for use of HPLC system; N. Mizushima for Atg5-deficient cells; A. Kazantsev for CBP and CBPΔQ constructs; Y. Yoshimori for GFP-LC3; G.A. Fitzgerald for p300 and P/CAF; P.W. Faber for osm::Htt564-150Q ; and the New York Structural Biology Center for the EM facilities. This work was supported by R01NS050352 and R01 NS051303 (to D.K.) and R01 NS050199 (to A.Y.). F.T. is a fellow of the DFG. Author contributions: H.J. and F.T. contributed equally to this work.

PY - 2009/4/3

Y1 - 2009/4/3

N2 - Huntington's disease (HD) is an incurable neurodegenerative disease caused by neuronal accumulation of the mutant protein huntingtin. Improving clearance of the mutant protein is expected to prevent cellular dysfunction and neurodegeneration in HD. We report here that such clearance can be achieved by posttranslational modification of the mutant Huntingtin (Htt) by acetylation at lysine residue 444 (K444). Increased acetylation at K444 facilitates trafficking of mutant Htt into autophagosomes, significantly improves clearance of the mutant protein by macroautophagy, and reverses the toxic effects of mutant huntingtin in primary striatal and cortical neurons and in a transgenic C. elegans model of HD. In contrast, mutant Htt that is rendered resistant to acetylation dramatically accumulates and leads to neurodegeneration in cultured neurons and in mouse brain. These studies identify acetylation as a mechanism for removing accumulated protein in HD, and more broadly for actively targeting proteins for degradation by autophagy.

AB - Huntington's disease (HD) is an incurable neurodegenerative disease caused by neuronal accumulation of the mutant protein huntingtin. Improving clearance of the mutant protein is expected to prevent cellular dysfunction and neurodegeneration in HD. We report here that such clearance can be achieved by posttranslational modification of the mutant Huntingtin (Htt) by acetylation at lysine residue 444 (K444). Increased acetylation at K444 facilitates trafficking of mutant Htt into autophagosomes, significantly improves clearance of the mutant protein by macroautophagy, and reverses the toxic effects of mutant huntingtin in primary striatal and cortical neurons and in a transgenic C. elegans model of HD. In contrast, mutant Htt that is rendered resistant to acetylation dramatically accumulates and leads to neurodegeneration in cultured neurons and in mouse brain. These studies identify acetylation as a mechanism for removing accumulated protein in HD, and more broadly for actively targeting proteins for degradation by autophagy.

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DO - 10.1016/j.cell.2009.03.018

M3 - Article

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SN - 0092-8674

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EP - 72

JO - Cell

JF - Cell

IS - 1

ER -

Acetylation Targets Mutant Huntingtin to Autophagosomes for Degradation

Abstract

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Keywords

ASJC Scopus subject areas

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