Atypical ubiquitination by E3 ligase WWP1 inhibits the proteasome-mediated degradation of mutant huntingtin.
Huntington's disease (HD) is caused by the expansion of CAG trinucleotide repeats in exon 1 of HD gene encoding huntingtin (Htt), which is characterized by aggregation and formation of mutant Htt containing expanded polyglutamine (polyQ) repeats. Dysfunction of the ubiquitin-proteasome system (UPS) plays a critical role in the pathogenesis of HD. As the linkage mediator between ubiquitin and specific target proteins, E3 ubiquitin ligases have been suggested to be involved in mHtt degradation and HD pathology. However, the potential involvement of the E3 ligase WWP1 in HD has not been explored. The present study determined whether WWP1 is involved in the development of HD in both in vivo and in vitro models. The results showed that in contrast to several other E3 ligases, expression of WWP1 is enhanced in mice and N2a cells expressing mutant Htt (160Q) and co-localized with mHtt protein aggregates. In addition, expression of WWP1 positively regulates mutan Htt levels, aggregate formation, and cell toxicity. Further analysis revealed that WWP1 ubiquitinated mHtt at an atypical position of Lys-63, which may have inhibited degradation of mutant Htt through the ubiquitin-proteasome pathway. In conclusion, these results suggested that the E3 ligase WWP1 is involved in the pathogenesis of HD; therefore, it may be a novel target for therapeutic intervention.
Division of Histology and Embryology, Department of Anatomy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
Li
L
Lin
Division of Histology and Embryology, Department of Anatomy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
Zhenzhen
Z
Jin
Division of Histology and Embryology, Department of Anatomy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
Huiping
H
Tan
Division of Histology and Embryology, Department of Anatomy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
Qiaoqiao
Q
Xu
Division of Histology and Embryology, Department of Anatomy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China; (b)Key Laboratory for Neurological Disorders of Education Ministry,Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China; (c)Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China. Electronic address: pengting@mail.hust.edu.cn.
Ting
T
Peng
Division of Histology and Embryology, Department of Anatomy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China; (b)Key Laboratory for Neurological Disorders of Education Ministry,Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China; (c)Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China. Electronic address: heli@mails.tjmu.edu.cn.
He
H
Li
D000818:Animals; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D002470:Cell Survival; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics / Q000378:metabolism*; D006816:Huntington Disease / Q000201:enzymology*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
C086055:HTT protein, human; D000071058:Huntingtin Protein; C510836:WWP1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex
E3 ligase; Huntingtin; Huntington's disease; Ubiquitin-proteasome system; Ubiquitination; WWP1