SUMO modification of Huntingtin and Huntington's disease pathology.
Huntington's disease (HD) is characterized by the accumulation of a pathogenic protein, Huntingtin (Htt), that contains an abnormal polyglutamine expansion. Here, we report that a pathogenic fragment of Htt (Httex1p) can be modified either by small ubiquitin-like modifier (SUMO)-1 or by ubiquitin on identical lysine residues. In cultured cells, SUMOylation stabilizes Httex1p, reduces its ability to form aggregates, and promotes its capacity to repress transcription. In a Drosophila model of HD, SUMOylation of Httex1p exacerbates neurodegeneration, whereas ubiquitination of Httex1p abrogates neurodegeneration. Lysine mutations that prevent both SUMOylation and ubiquitination of Httex1p reduce HD pathology, indicating that the contribution of SUMOylation to HD pathology extends beyond preventing Htt ubiquitination and degradation.
Steffan
Joan S
JS
Department of Psychiatry and Human Behavior, Gillespie 2121, University of California, Irvine, CA 92697, USA.
Agrawal
Namita
N
Pallos
Judit
J
Rockabrand
Erica
E
Trotman
Lloyd C
LC
Slepko
Natalia
N
Illes
Katalin
K
Lukacsovich
Tamas
T
Zhu
Ya-Zhen
YZ
Cattaneo
Elena
E
Pandolfi
Pier Paolo
PP
Thompson
Leslie Michels
LM
Marsh
J Lawrence
JL
D000818:Animals; D030801:Animals, Genetically Modified; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003342:Corpus Striatum / Q000166:cytology; D003593:Cytoplasm / Q000378:metabolism; D004330:Drosophila; D019450:Genes, MDR; D006367:HeLa Cells; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism / Q000473:pathology*; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009410:Nerve Degeneration; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011392:Proline / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism
C086055:HTT protein, human; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D025842:SUMO-1 Protein; D025801:Ubiquitin; D011392:Proline; D008239:Lysine