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.
authors.affiliation: Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Jacqueline Gire
authors.initials: JG
authors.lastname: O'Rourke
authors.forename: Jaclyn R
authors.initials: JR
authors.lastname: Gareau
authors.forename: Joseph
authors.initials: J
authors.lastname: Ochaba
authors.forename: Wan
authors.initials: W
authors.lastname: Song
authors.forename: Tamás
authors.initials: T
authors.lastname: Raskó
authors.forename: David
authors.initials: D
authors.lastname: Reverter
authors.forename: John
authors.initials: J
authors.lastname: Lee
authors.forename: Alex Mas
authors.initials: AM
authors.lastname: Monteys
authors.forename: Judit
authors.initials: J
authors.lastname: Pallos
authors.forename: Lisa
authors.initials: L
authors.lastname: Mee
authors.forename: Malini
authors.initials: M
authors.lastname: Vashishtha
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Apostol
authors.forename: Thomas Peter
authors.initials: TP
authors.lastname: Nicholson
authors.forename: Katalin
authors.initials: K
authors.lastname: Illes
authors.forename: Ya-Zhen
authors.initials: YZ
authors.lastname: Zhu
authors.forename: Mary
authors.initials: M
authors.lastname: Dasso
authors.forename: Gillian P
authors.initials: GP
authors.lastname: Bates
authors.forename: Marian
authors.initials: M
authors.lastname: Difiglia
authors.forename: Beverly
authors.initials: B
authors.lastname: Davidson
authors.forename: Erich E
authors.initials: EE
authors.lastname: Wanker
authors.forename: J Lawrence
authors.initials: JL
authors.lastname: Marsh
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Lima
authors.forename: Joan S
authors.initials: JS
authors.lastname: Steffan
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Thompson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D004330:Drosophila; D005260:Female; D006367:HeLa Cells; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; C106529:PIAS1 protein, human; D050828:Protein Inhibitors of Activated STAT; C117909:SUMO2 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; D044767:Ubiquitin-Protein Ligases