SUMO-2 and PIAS1 Modulate Insoluble Mutant Huntingtin Protein Accumulation

Jacqueline Gire O'Rourke; Jaclyn R. Gareau; Joseph Ochaba; Wan Song; Tamas Rasko; David Reverter; John Lee; Alex Mas Monteys; Judit Pallos; Lisa Mee; Malini Vashishtha; Barbara L. Apostol; Thomas Peter Nicholson; Katalin Illes; Ya-Zhen Zhu; Mary Dasso; Gillian P. Bates; Marian Difiglia; Beverly Davidson; Erich E. Wanker; J. Lawrence Marsh; Christopher D. Lima; Joan S. Steffan; Leslie M. Thompson

doi:10.1016/j.celrep.2013.06.034

SUMO-2 and PIAS1 Modulate Insoluble Mutant Huntingtin Protein Accumulation

Jacqueline Gire O'Rourke, Jaclyn R. Gareau, Joseph Ochaba, Wan Song, Tamas Rasko, David Reverter, John Lee, Alex Mas Monteys, Judit Pallos, Lisa Mee, Malini Vashishtha, Barbara L. Apostol, Thomas Peter Nicholson, Katalin Illes, Ya-Zhen Zhu, Mary Dasso, Gillian P. Bates, Marian Difiglia, Beverly Davidson, Erich E. WankerJ. Lawrence Marsh, Christopher D. Lima, Joan S. Steffan, Leslie M. Thompson^*

^*Corresponding author for this work

Medical & Molecular Genetics

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

88 Citations (Scopus)

Abstract

A key feature in Huntington disease (HD) is the accumulation of mutant Huntingtin (HTT) protein, which may be regulated by posttranslational modifications. Here, we define the primary sites of SUMO modification in the amino-terminal domain of HTT, show modification downstream of this domain, and demonstrate that HTT is modified by the stress-inducible SUMO-2. A systematic study of E3 SUMO ligases demonstrates that PIAS1 is an E3 SUMO ligase for both HTT SUMO-1 and SUMO-2 modification and that reduction of dPIAS in a mutant HTT Drosophila model is protective. SUMO-2 modification regulates accumulation of insoluble HTT in HeLa cells in a manner that mimics proteasome inhibition and can be modulated by overexpression and acute knockdown of PIAS1. Finally, the accumulation of SUMO-2-modified proteins in the insoluble fraction of HD postmortem striata implicates SUMO-2 modification in the age-related pathogenic accumulation of mutant HTT and other cellular proteins that occurs during HD progression.

Original language	English
Article number	N/A
Pages (from-to)	362-375
Number of pages	14
Journal	Cell Reports
Volume	4
Issue number	2
DOIs	https://doi.org/10.1016/j.celrep.2013.06.034
Publication status	Published - 25 Jul 2013

Keywords

DISEASE PATHOGENESIS
POSTTRANSLATIONAL MODIFICATIONS
INTERACTION NETWORK
CONJUGATION
AGGREGATION
SUMOYLATION
REPEAT
MICE
GENE
ACTIVATION

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10.1016/j.celrep.2013.06.034

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O'Rourke, J. G., Gareau, J. R., Ochaba, J., Song, W., Rasko, T., Reverter, D., Lee, J., Monteys, A. M., Pallos, J., Mee, L., Vashishtha, M., Apostol, B. L., Nicholson, T. P., Illes, K., Zhu, Y.-Z., Dasso, M., Bates, G. P., Difiglia, M., Davidson, B., ... Thompson, L. M. (2013). SUMO-2 and PIAS1 Modulate Insoluble Mutant Huntingtin Protein Accumulation. Cell Reports, 4(2), 362-375. Article N/A. https://doi.org/10.1016/j.celrep.2013.06.034

@article{d29299f85db84c24a30fc72d547c7f67,

title = "SUMO-2 and PIAS1 Modulate Insoluble Mutant Huntingtin Protein Accumulation",

abstract = "A key feature in Huntington disease (HD) is the accumulation of mutant Huntingtin (HTT) protein, which may be regulated by posttranslational modifications. Here, we define the primary sites of SUMO modification in the amino-terminal domain of HTT, show modification downstream of this domain, and demonstrate that HTT is modified by the stress-inducible SUMO-2. A systematic study of E3 SUMO ligases demonstrates that PIAS1 is an E3 SUMO ligase for both HTT SUMO-1 and SUMO-2 modification and that reduction of dPIAS in a mutant HTT Drosophila model is protective. SUMO-2 modification regulates accumulation of insoluble HTT in HeLa cells in a manner that mimics proteasome inhibition and can be modulated by overexpression and acute knockdown of PIAS1. Finally, the accumulation of SUMO-2-modified proteins in the insoluble fraction of HD postmortem striata implicates SUMO-2 modification in the age-related pathogenic accumulation of mutant HTT and other cellular proteins that occurs during HD progression.",

keywords = "DISEASE PATHOGENESIS, POSTTRANSLATIONAL MODIFICATIONS, INTERACTION NETWORK, CONJUGATION, AGGREGATION, SUMOYLATION, REPEAT, MICE, GENE, ACTIVATION",

author = "O'Rourke, {Jacqueline Gire} and Gareau, {Jaclyn R.} and Joseph Ochaba and Wan Song and Tamas Rasko and David Reverter and John Lee and Monteys, {Alex Mas} and Judit Pallos and Lisa Mee and Malini Vashishtha and Apostol, {Barbara L.} and Nicholson, {Thomas Peter} and Katalin Illes and Ya-Zhen Zhu and Mary Dasso and Bates, {Gillian P.} and Marian Difiglia and Beverly Davidson and Wanker, {Erich E.} and Marsh, {J. Lawrence} and Lima, {Christopher D.} and Steffan, {Joan S.} and Thompson, {Leslie M.}",

year = "2013",

month = jul,

day = "25",

doi = "10.1016/j.celrep.2013.06.034",

language = "English",

volume = "4",

pages = "362--375",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Elsevier BV",

number = "2",

}

O'Rourke, JG, Gareau, JR, Ochaba, J, Song, W, Rasko, T, Reverter, D, Lee, J, Monteys, AM, Pallos, J, Mee, L, Vashishtha, M, Apostol, BL, Nicholson, TP, Illes, K, Zhu, Y-Z, Dasso, M, Bates, GP, Difiglia, M, Davidson, B, Wanker, EE, Marsh, JL, Lima, CD, Steffan, JS & Thompson, LM 2013, 'SUMO-2 and PIAS1 Modulate Insoluble Mutant Huntingtin Protein Accumulation', Cell Reports, vol. 4, no. 2, N/A, pp. 362-375. https://doi.org/10.1016/j.celrep.2013.06.034

TY - JOUR

T1 - SUMO-2 and PIAS1 Modulate Insoluble Mutant Huntingtin Protein Accumulation

AU - O'Rourke, Jacqueline Gire

AU - Gareau, Jaclyn R.

AU - Ochaba, Joseph

AU - Song, Wan

AU - Rasko, Tamas

AU - Reverter, David

AU - Lee, John

AU - Monteys, Alex Mas

AU - Pallos, Judit

AU - Mee, Lisa

AU - Vashishtha, Malini

AU - Apostol, Barbara L.

AU - Nicholson, Thomas Peter

AU - Illes, Katalin

AU - Zhu, Ya-Zhen

AU - Dasso, Mary

AU - Bates, Gillian P.

AU - Difiglia, Marian

AU - Davidson, Beverly

AU - Wanker, Erich E.

AU - Marsh, J. Lawrence

AU - Lima, Christopher D.

AU - Steffan, Joan S.

AU - Thompson, Leslie M.

PY - 2013/7/25

Y1 - 2013/7/25

N2 - A key feature in Huntington disease (HD) is the accumulation of mutant Huntingtin (HTT) protein, which may be regulated by posttranslational modifications. Here, we define the primary sites of SUMO modification in the amino-terminal domain of HTT, show modification downstream of this domain, and demonstrate that HTT is modified by the stress-inducible SUMO-2. A systematic study of E3 SUMO ligases demonstrates that PIAS1 is an E3 SUMO ligase for both HTT SUMO-1 and SUMO-2 modification and that reduction of dPIAS in a mutant HTT Drosophila model is protective. SUMO-2 modification regulates accumulation of insoluble HTT in HeLa cells in a manner that mimics proteasome inhibition and can be modulated by overexpression and acute knockdown of PIAS1. Finally, the accumulation of SUMO-2-modified proteins in the insoluble fraction of HD postmortem striata implicates SUMO-2 modification in the age-related pathogenic accumulation of mutant HTT and other cellular proteins that occurs during HD progression.

AB - A key feature in Huntington disease (HD) is the accumulation of mutant Huntingtin (HTT) protein, which may be regulated by posttranslational modifications. Here, we define the primary sites of SUMO modification in the amino-terminal domain of HTT, show modification downstream of this domain, and demonstrate that HTT is modified by the stress-inducible SUMO-2. A systematic study of E3 SUMO ligases demonstrates that PIAS1 is an E3 SUMO ligase for both HTT SUMO-1 and SUMO-2 modification and that reduction of dPIAS in a mutant HTT Drosophila model is protective. SUMO-2 modification regulates accumulation of insoluble HTT in HeLa cells in a manner that mimics proteasome inhibition and can be modulated by overexpression and acute knockdown of PIAS1. Finally, the accumulation of SUMO-2-modified proteins in the insoluble fraction of HD postmortem striata implicates SUMO-2 modification in the age-related pathogenic accumulation of mutant HTT and other cellular proteins that occurs during HD progression.

KW - DISEASE PATHOGENESIS

KW - POSTTRANSLATIONAL MODIFICATIONS

KW - INTERACTION NETWORK

KW - CONJUGATION

KW - AGGREGATION

KW - SUMOYLATION

KW - REPEAT

KW - MICE

KW - GENE

KW - ACTIVATION

U2 - 10.1016/j.celrep.2013.06.034

DO - 10.1016/j.celrep.2013.06.034

M3 - Article

SN - 2211-1247

VL - 4

SP - 362

EP - 375

JO - Cell Reports

JF - Cell Reports

IS - 2

M1 - N/A

ER -

SUMO-2 and PIAS1 Modulate Insoluble Mutant Huntingtin Protein Accumulation

Abstract

Keywords

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