Huntingtin is present in the nucleus, interacts with the transcriptional corepressor C-terminal binding protein, and represses transcription.
Huntingtin is a protein of unknown function that contains a polyglutamine tract, which is expanded in patients with Huntington's disease (HD). We investigated the localization and a potential function for huntingtin in the nucleus. In human fibroblasts from normal and HD patients, huntingtin localized diffusely in the nucleus and in subnuclear compartments identified as speckles, promyelocytic leukemia protein bodies, and nucleoli. Huntingtin-positive nuclear bodies redistributed after treatment with sodium butyrate. By Western blot, purified nuclei had low levels of full-length huntingtin compared with the cytoplasm but contained high levels of N- and C-terminal huntingtin fragments, which tightly bound the nuclear matrix. Full-length huntingtin co-immunoprecipitated with the transcriptional corepressor C-terminal binding protein, and polyglutamine expansion in huntingtin reduced this interaction. Full-length wild-type and mutant huntingtin repressed transcription when targeted to DNA. Truncated N-terminal mutant huntingtin repressed transcription, whereas the corresponding wild-type fragment did not repress transcription. We speculate that wild-type huntingtin may function in the nucleus in the assembly of nuclear matrix-bound protein complexes involved with transcriptional repression and RNA processing. Proteolysis of mutant huntingtin may alter nuclear functions by disrupting protein complexes and inappropriately repressing transcription in HD.
Kegel
Kimberly B
KB
Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA. kegel@helix.mgh.harvard.edu
Meloni
Alison R
AR
Yi
Yong
Y
Kim
Yun J
YJ
Doyle
Erin
E
Cuiffo
Benjamin G
BG
Sapp
Ellen
E
Wang
Yumei
Y
Qin
Zheng-Hong
ZH
Chen
J Don
JD
Nevins
Joseph R
JR
Aronin
Neil
N
DiFiglia
Marian
M
D000429:Alcohol Oxidoreductases; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D019556:COS Cells; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D000939:Epitopes; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D018613:Microscopy, Confocal; D008957:Models, Genetic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D009687:Nuclear Proteins / Q000096:biosynthesis*; D010455:Peptides / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012313:RNA / Q000378:metabolism; D012978:Sodium Oxybate / Q000494:pharmacology; D014158:Transcription, Genetic; D014162:Transfection
D004268:DNA-Binding Proteins; D000939:Epitopes; C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D010750:Phosphoproteins; C097188:polyglutamine; D012313:RNA; D012978:Sodium Oxybate; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein