SUMO-2 and PIAS1 modulate insoluble mutant huntingtin protein accumulation
O'Rourke, Jacqueline Gire (University of California)
Gareau, Jaclyn R. (Sloan-Kettering Institute)
Ochaba, Joseph (University of California)
Song, Wan (University of California)
Raskó, Tamás (Max-Delbrueck-Center for Molecular Medicine)
Reverter i Cendrós, David (Sloan-Kettering Institute)
Lee, John (University of Iowa)
Mas Monteys, Alexandre (University of Iowa)
Pallos, Judit (University of California)
Mee, Lisa (University of California)
Vashishtha, Malini (University of California)
Apostol, Barbara L. (University of California)
Nicholson, Thomas Peter (Enzo Life Sciences Ltd.)
Illes, Katalin (University of California)
Zhu, Ya-Zhen (University of California)
Dasso, Mary (National Institute of Child Health and Development)
Bates, Gillian P. (King's College London)
Difiglia, Marian (Harvard Medical School)
Davidson, Beverly (University of Iowa)
Wanker, Erich E. (Max-Delbrueck-Center for Molecular Medicine)
Marsh, J. Lawrence (University of California)
Lima, Christopher D. (Sloan-Kettering Institute)
Steffan, Joan S. (University of California)
Thompson, Leslie M. (University of California.)

Date:	2013
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 SUMOmodification 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 anE3 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.
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Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Published in:	Cell reports, Vol. 4, Issue 2 (July 2013) , p. 362-375, ISSN 2211-1247

DOI: 10.1016/j.celrep.2013.06.034
PMID: 23871671

14 p, 2.3 MB

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