Bax-inhibiting peptide protects cells from polyglutamine toxicity caused by Ku70 acetylation.
Polyglutamine (polyQ) diseases, such as Huntington's disease and Machado-Joseph disease (MJD), are caused by gain of toxic function of abnormally expanded polyQ tracts. Here, we show that expanded polyQ of ataxin-3 (Q79C), a gene that causes MJD, stimulates Ku70 acetylation, which in turn dissociates the proapoptotic protein Bax from Ku70, thereby promoting Bax activation and subsequent cell death. The Q79C-induced cell death was significantly blocked by Ku70 or Bax-inhibiting peptides (BIPs) designed from Ku70. Furthermore, expression of SIRT1 deacetylase and the addition of a SIRT1 agonist, resveratrol, reduced Q79C toxicity. In contrast, mimicking acetylation of Ku70 abolished the ability of Ku70 to suppress Q79C toxicity. These results indicate that Bax and Ku70 acetylation play important roles in Q79C-induced cell death, and that BIP may be useful in the development of therapeutics for polyQ diseases.
Li
Y
Y
Department of Neurology and Neurological Science, Tokyo Medical and Dental University, Tokyo, Japan.
Yokota
T
T
Gama
V
V
Yoshida
T
T
Gomez
J A
JA
Ishikawa
K
K
Sasaguri
H
H
Cohen
H Y
HY
Sinclair
D A
DA
Mizusawa
H
H
Matsuyama
S
S
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects*; D053938:DNA Fragmentation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D000072200:Ku Autoantigen; D050505:Mutant Proteins / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology* / Q000633:toxicity; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology; D014617:Vacuoles / Q000187:drug effects / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors*
D034961:Antigens, Nuclear; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D050505:Mutant Proteins; D010455:Peptides; D013267:Stilbenes; D051028:bcl-2-Associated X Protein; C097188:polyglutamine; D051548:Histone Acetyltransferases; D020169:Caspases; C000606509:Xrcc6 protein, human; C000606511:Xrcc6 protein, rat; D000072200:Ku Autoantigen; D000077185:Resveratrol