Differential ubiquitination and degradation of huntingtin fragments modulated by ubiquitin-protein ligase E3A.
Ubiquitination of misfolded proteins, a common feature of many neurodegenerative diseases, is mediated by different lysine (K) residues in ubiquitin and alters the levels of toxic proteins. In Huntington disease, polyglutamine expansion causes N-terminal huntingtin (Htt) to misfold, inducing neurodegeneration. Here we report that shorter N-terminal Htt fragments are more stable than longer fragments and find differential ubiquitination via K63 of ubiquitin. Aging decreases proteasome-mediated Htt degradation, at the same time increasing K63-mediated ubiquitination and subsequent Htt aggregation in HD knock-in mice. The association of Htt with the K48-specific E3 ligase, Ube3a, is decreased in aged mouse brain. Overexpression of Ube3a in HD mouse brain reduces K63-mediated ubiquitination and Htt aggregation, enhancing its degradation via the K48 ubiquitin-proteasome system. Our findings suggest that aging-dependent Ube3a levels result in differential ubiquitination and degradation of Htt fragments, thereby contributing to the age-related neurotoxicity of mutant Htt.
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322.
Kavita P
KP
Bhat
Sen
S
Yan
Chuan-En
CE
Wang
Shihua
S
Li
Xiao-Jiang
XJ
Li
D000367:Age Factors; D000818:Animals; D003513:Cycloheximide; D005455:Fluorescent Antibody Technique; D055879:Gene Knock-In Techniques; D057809:HEK293 Cells; D006801:Humans; D000071058:Huntingtin Protein; D047468:Immunoprecipitation; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D059748:Proteolysis; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*
C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D003513:Cycloheximide; C502429:Ube3a protein, mouse; D044767:Ubiquitin-Protein Ligases
misfolding; proteolysis