TY - JOUR
T1 - Molecular clearance of ataxin-3 is regulated by a mammalian E4
AU - Matsumoto, Masaki
AU - Yada, Masayoshi
AU - Hatakeyama, Shigetsugu
AU - Ishimoto, Hiroshi
AU - Tanimura, Teiichi
AU - Tsuji, Shoji
AU - Kakizuka, Akira
AU - Kitagawa, Masatoshi
AU - Nakayama, Keiichi I.
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2004/2/11
Y1 - 2004/2/11
N2 - Insoluble aggregates of polyglutamine-containing proteins are usually conjugated with ubiquitin in neurons of individuals with polyglutamine diseases. We now show that ataxin-3, in which the abnormal expansion of a polyglutamine tract is responsible for spinocerebellar ataxia type 3 (SCA3), undergoes ubiquitylation and degradation by the proteasome. Mammalian E4B (UFD2a), a ubiquitin chain assembly factor (E4), copurified with the polyubiquitylation activity for ataxin-3. E4B interacted with, and thereby mediated polyubiquitylation of, ataxin-3. Expression of E4B promoted degradation of a pathological form of ataxin-3. In contrast, a dominant-negative mutant of E4B inhibited degradation of this form of ataxin-3, resulting in the formation of intracellular aggregates. In a Drosophila model of SCA3, expression of E4B suppressed the neurodegeneration induced by an ataxin-3 mutant. These observations suggest that E4 is a rate-limiting factor in the degradation of pathological forms of ataxin-3, and that targeted expression of E4B is a potential gene therapy for SCA3.
AB - Insoluble aggregates of polyglutamine-containing proteins are usually conjugated with ubiquitin in neurons of individuals with polyglutamine diseases. We now show that ataxin-3, in which the abnormal expansion of a polyglutamine tract is responsible for spinocerebellar ataxia type 3 (SCA3), undergoes ubiquitylation and degradation by the proteasome. Mammalian E4B (UFD2a), a ubiquitin chain assembly factor (E4), copurified with the polyubiquitylation activity for ataxin-3. E4B interacted with, and thereby mediated polyubiquitylation of, ataxin-3. Expression of E4B promoted degradation of a pathological form of ataxin-3. In contrast, a dominant-negative mutant of E4B inhibited degradation of this form of ataxin-3, resulting in the formation of intracellular aggregates. In a Drosophila model of SCA3, expression of E4B suppressed the neurodegeneration induced by an ataxin-3 mutant. These observations suggest that E4 is a rate-limiting factor in the degradation of pathological forms of ataxin-3, and that targeted expression of E4B is a potential gene therapy for SCA3.
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U2 - 10.1038/sj.emboj.7600081
DO - 10.1038/sj.emboj.7600081
M3 - Article
C2 - 14749733
AN - SCOPUS:1442264782
VL - 23
SP - 659
EP - 669
JO - EMBO Journal
JF - EMBO Journal
SN - 0261-4189
IS - 3
ER -