IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome.
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.
Thompson
Leslie Michels
LM
Department of Psychiatry and Human Behavior, University of California, Irvine, 92697, USA.
Aiken
Charity T
CT
Kaltenbach
Linda S
LS
Agrawal
Namita
N
Illes
Katalin
K
Khoshnan
Ali
A
Martinez-Vincente
Marta
M
Arrasate
Montserrat
M
O'Rourke
Jacqueline Gire
JG
Khashwji
Hasan
H
Lukacsovich
Tamas
T
Zhu
Ya-Zhen
YZ
Lau
Alice L
AL
Massey
Ashish
A
Hayden
Michael R
MR
Zeitlin
Scott O
SO
Finkbeiner
Steven
S
Green
Kim N
KN
LaFerla
Frank M
FM
Bates
Gillian
G
Huang
Lan
L
Patterson
Paul H
PH
Lo
Donald C
DC
Cuervo
Ana Maria
AM
Marsh
J Lawrence
JL
Steffan
Joan S
JS
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
C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D051550:I-kappa B Kinase; D046988:Proteasome Endopeptidase Complex