NUB1 suppresses the formation of Lewy body-like inclusions by proteasomal degradation of synphilin-1.
NUB1 is a potent down-regulator of the ubiquitin-like protein NEDD8, because it targets NEDD8 to the proteasome for proteolytic degradation. From results in this study, we found that NUB1 physically interacts with synphilin-1 through its NEDD8-binding site, implying that NUB1 also targets synphilin-1 to the proteasome for degradation. Synphilin-1 is a major component of inclusion bodies found in the brains of patients with neurodegenerative alpha-synucleinopathies, including Parkinson's disease. In this study, we immunostained sections of brains from patients with Parkinson's disease and other alpha-synucleinopathies and demonstrated that NUB1, as well as synphilin-1, accumulates in the inclusion bodies. To define the role of NUB1 in the formation of these inclusion bodies, we performed a co-transfection assay using cultured HEK293 cells. This assay showed that NUB1 suppresses the formation of synphilin-1-positive inclusions. Further, biochemical assays revealed that NUB1 overexpression leads to the proteasomal degradation of synphilin-1. These results and our previous observations suggest that NUB1 indeed targets synphilin-1 to the proteasome for its efficient degradation, which, because of the resultant reduction in synphilin-1, suppresses the formation of synphilin-1-positive inclusions.
Tanji
Kunikazu
K
Department of Cardiology, Unit 1101, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Tanaka
Tomoaki
T
Mori
Fumiaki
F
Kito
Katsumi
K
Takahashi
Hitoshi
H
Wakabayashi
Koichi
K
Kamitani
Tetsu
T
D048868:Adaptor Proteins, Signal Transducing; D001665:Binding Sites; D001921:Brain / Q000166:cytology / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics; D020869:Gene Expression Profiling; D019791:Guanidine / Q000378:metabolism; D006801:Humans; D016631:Lewy Bodies / Q000378:metabolism* / Q000473:pathology; D000075687:NEDD8 Protein; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012967:Sodium Dodecyl Sulfate / Q000378:metabolism; D012995:Solubility; D012996:Solutions; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism; D014508:Urea / Q000378:metabolism; D015003:Yeasts / Q000166:cytology; D051844:alpha-Synuclein / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; C430242:NUB1 protein, human; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C118958:SNCAIP protein, human; D012996:Solutions; D014157:Transcription Factors; D014452:Ubiquitins; D051844:alpha-Synuclein; D012967:Sodium Dodecyl Sulfate; D014508:Urea; D046988:Proteasome Endopeptidase Complex; D019791:Guanidine