title: IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome.
abstract: Expansion of the polyglutamine repeat within the protein Huntingtin (Htt) causes Huntington's disease, a neurodegenerative disease associated with aging and the accumulation of mutant Htt in diseased neurons. Understanding the mechanisms that influence Htt cellular degradation may target treatments designed to activate mutant Htt clearance pathways. We find that Htt is phosphorylated by the inflammatory kinase IKK, enhancing its normal clearance by the proteasome and lysosome. Phosphorylation of Htt regulates additional post-translational modifications, including Htt ubiquitination, SUMOylation, and acetylation, and increases Htt nuclear localization, cleavage, and clearance mediated by lysosomal-associated membrane protein 2A and Hsc70. We propose that IKK activates mutant Htt clearance until an age-related loss of proteasome/lysosome function promotes accumulation of toxic post-translationally modified mutant Htt. Thus, IKK activation may modulate mutant Htt neurotoxicity depending on the cell's ability to degrade the modified species.
authors.affiliation: Department of Psychiatry and Human Behavior, University of California, Irvine, 92697, USA.
authors.forename: Leslie Michels
authors.initials: LM
authors.lastname: Thompson
authors.forename: Charity T
authors.initials: CT
authors.lastname: Aiken
authors.forename: Linda S
authors.initials: LS
authors.lastname: Kaltenbach
authors.forename: Namita
authors.initials: N
authors.lastname: Agrawal
authors.forename: Katalin
authors.initials: K
authors.lastname: Illes
authors.forename: Ali
authors.initials: A
authors.lastname: Khoshnan
authors.forename: Marta
authors.initials: M
authors.lastname: Martinez-Vincente
authors.forename: Montserrat
authors.initials: M
authors.lastname: Arrasate
authors.forename: Jacqueline Gire
authors.initials: JG
authors.lastname: O'Rourke
authors.forename: Hasan
authors.initials: H
authors.lastname: Khashwji
authors.forename: Tamas
authors.initials: T
authors.lastname: Lukacsovich
authors.forename: Ya-Zhen
authors.initials: YZ
authors.lastname: Zhu
authors.forename: Alice L
authors.initials: AL
authors.lastname: Lau
authors.forename: Ashish
authors.initials: A
authors.lastname: Massey
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
authors.forename: Scott O
authors.initials: SO
authors.lastname: Zeitlin
authors.forename: Steven
authors.initials: S
authors.lastname: Finkbeiner
authors.forename: Kim N
authors.initials: KN
authors.lastname: Green
authors.forename: Frank M
authors.initials: FM
authors.lastname: LaFerla
authors.forename: Gillian
authors.initials: G
authors.lastname: Bates
authors.forename: Lan
authors.initials: L
authors.lastname: Huang
authors.forename: Paul H
authors.initials: PH
authors.lastname: Patterson
authors.forename: Donald C
authors.initials: DC
authors.lastname: Lo
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Cuervo
authors.forename: J Lawrence
authors.initials: JL
authors.lastname: Marsh
authors.forename: Joan S
authors.initials: JS
authors.lastname: Steffan
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D000071058:Huntingtin Protein; D051550:I-kappa B Kinase / Q000502:physiology*; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D009687:Nuclear Proteins / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D054875:Ubiquitination
chemical_list: C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D051550:I-kappa B Kinase; D046988:Proteasome Endopeptidase Complex