Cellular toxicity of polyglutamine expansion proteins: mechanism of transcription factor deactivation.
The expression of polyglutamine-expanded mutant proteins in Huntington's disease and other neurodegenerative disorders is associated with the formation of intraneural inclusions. These aggregates could potentially cause cellular toxicity by sequestering essential proteins possessing normal polyQ repeats, including the transcription factors TBP and CBP. We show, in vitro and in cells, that monomers or small soluble oligomers of huntingtin exon1 accumulate in the nucleus and inhibit the function of TBP in a polyQ-dependent manner. FRET experiments indicate that these toxic forms are generated through a conformational rearrangement in huntingtin. Interaction of toxic huntingtin with the benign polyQ repeat of TBP structurally destabilizes the transcription factor, independent of the formation of insoluble coaggregates. Hsp70/Hsp40 chaperones interfere with the conformational change in mutant huntingtin and inhibit the deactivation of TBP. These results outline a molecular mechanism of cellular toxicity in polyQ disease and can explain the beneficial effects of molecular chaperones.
Schaffar
Gregor
G
Department of Cellular Biochemistry, Max-Planck Institute of Biochemistry, Am Klopferspitz 18, D-82152 Martinsried, Germany.
Breuer
Peter
P
Boteva
Raina
R
Behrends
Christian
C
Tzvetkov
Nikolay
N
Strippel
Nadine
N
Sakahira
Hideki
H
Siegers
Katja
K
Hayer-Hartl
Manajit
M
Hartl
F Ulrich
FU
D000818:Animals; D050882:CREB-Binding Protein; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D005091:Exons; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D000071058:Huntingtin Protein; D046911:Macromolecular Substances; D051379:Mice; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D010455:Peptides / Q000235:genetics* / Q000378:metabolism; D011487:Protein Conformation; D017510:Protein Folding; D012441:Saccharomyces cerevisiae; D035181:TATA-Box Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
D018840:HSP70 Heat-Shock Proteins; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D046911:Macromolecular Substances; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D035181:TATA-Box Binding Protein; D015534:Trans-Activators; D014157:Transcription Factors; C097188:polyglutamine; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse