SUMO-2 and PIAS1 Modulate Insoluble Mutant Huntingtin Protein Accumulation
Jacqueline Gire O’Rourke,
Jaclyn R. Gareau,
Joseph Ochaba,
Wan Song,
Tamás Raskó,
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
Affiliations
Jacqueline Gire O’Rourke
Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA
Jaclyn R. Gareau
Structural Biology Program, Sloan-Kettering Institute, New York, NY 10065, USA
Joseph Ochaba
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697, USA
Wan Song
Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, USA
Tamás Raskó
Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany
David Reverter
Structural Biology Program, Sloan-Kettering Institute, New York, NY 10065, USA
John Lee
Departments of Internal Medicine, Neurology, and Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Alex Mas Monteys
Departments of Internal Medicine, Neurology, and Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Judit Pallos
Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, USA
Lisa Mee
Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, CA 92697, USA
Malini Vashishtha
Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, CA 92697, USA
Barbara L. Apostol
Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, CA 92697, USA
Thomas Peter Nicholson
Enzo Life Sciences (UK) Ltd., Palatine House, Matford Court, Exeter EX2 8NL, UK
Katalin Illes
Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, CA 92697, USA
Ya-Zhen Zhu
Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, CA 92697, USA
Mary Dasso
Laboratory of Gene Regulation and Development, National Institute of Child Health and Development, National Institutes of Health, Bethesda, MD 20892, USA
Gillian P. Bates
Department of Medical and Molecular Genetics, King’s College London School of Medicine, London WC2R 2LS, UK
Marian Difiglia
Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
Beverly Davidson
Departments of Internal Medicine, Neurology, and Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Erich E. Wanker
Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany
J. Lawrence Marsh
Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, USA
Christopher D. Lima
Structural Biology Program, Sloan-Kettering Institute, New York, NY 10065, USA
Joan S. Steffan
Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, CA 92697, USA
Leslie M. Thompson
Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA
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.
