IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome

• Published in: The Journal of cell biology Vol. 187; no. 7; pp. 1083 - 1099
• Main Authors: Thompson, Leslie Michels, Aiken, Charity T, Kaltenbach, Linda S, Agrawal, Namita, Illes, Katalin, Khoshnan, Ali, Martinez-Vincente, Marta, Arrasate, Montserrat, O'Rourke, Jacqueline Gire, Khashwji, Hasan, Lukacsovich, Tamas, Zhu, Ya-Zhen, Lau, Alice L, Massey, Ashish, Hayden, Michael R, Zeitlin, Scott O, Finkbeiner, Steven, Green, Kim N, LaFerla, Frank M, Bates, Gillian, Huang, Lan, Patterson, Paul H, Lo, Donald C, Cuervo, Ana Maria, Marsh, J. Lawrence, Steffan, Joan S
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 28.12.2009; Rockefeller University Press
• Subjects: Acetylation; Aging; Animals; Antibodies; Brain - metabolism; Cell culture techniques; Cell Line; Cells; Genetic disorders; Humans; Huntingtin Protein; Huntington disease; I-kappa B Kinase - physiology; Kinases; Lysosomes; Lysosomes - metabolism; Mice; Mutation; Nerve Tissue Proteins - analysis; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - metabolism; Nervous system diseases; Neurological disorders; Neurons; Nuclear Proteins - analysis; Nuclear Proteins - chemistry; Nuclear Proteins - metabolism; Phosphorylation; Physiological regulation; Proteasome Endopeptidase Complex - metabolism; Protein Structure, Tertiary; Proteins; Rats; Rats, Sprague-Dawley; Solubility; Ubiquitination
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.200909067

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.