NRBP1-Containing CRL2/CRL4A Regulates Amyloid β Production by Targeting BRI2 and BRI3 for Degradation
Summary: Alzheimer’s disease (AD) is a progressive neurodegenerative disease caused by accumulations of Aβ peptides. Production and fibrillation of Aβ are downregulated by BRI2 and BRI3, which are physiological inhibitors of amyloid precursor protein (APP) processing and Aβ oligomerization. Here, we...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-03-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124720302278 |
| _version_ | 1818919850467131392 |
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| author | Takashi Yasukawa Aya Tsutsui Chieri Tomomori-Sato Shigeo Sato Anita Saraf Michael P. Washburn Laurence Florens Tohru Terada Kentaro Shimizu Ronald C. Conaway Joan W. Conaway Teijiro Aso |
| author_facet | Takashi Yasukawa Aya Tsutsui Chieri Tomomori-Sato Shigeo Sato Anita Saraf Michael P. Washburn Laurence Florens Tohru Terada Kentaro Shimizu Ronald C. Conaway Joan W. Conaway Teijiro Aso |
| author_sort | Takashi Yasukawa |
| collection | DOAJ |
| description | Summary: Alzheimer’s disease (AD) is a progressive neurodegenerative disease caused by accumulations of Aβ peptides. Production and fibrillation of Aβ are downregulated by BRI2 and BRI3, which are physiological inhibitors of amyloid precursor protein (APP) processing and Aβ oligomerization. Here, we identify nuclear receptor binding protein 1 (NRBP1) as a substrate receptor of a Cullin-RING ubiquitin ligase (CRL) that targets BRI2 and BRI3 for degradation. Moreover, we demonstrate that (1) dimerized NRBP1 assembles into a functional Cul2- and Cul4A-containing heterodimeric CRL through its BC-box and an overlapping cryptic H-box, (2) both Cul2 and Cul4A contribute to NRBP1 CRL function, and (3) formation of the NRBP1 heterodimeric CRL is strongly enhanced by chaperone-like function of TSC22D3 and TSC22D4. NRBP1 knockdown in neuronal cells results in an increase in the abundance of BRI2 and BRI3 and significantly reduces Aβ production. Thus, disrupting interactions between NRBP1 and its substrates BRI2 and BRI3 may provide a useful therapeutic strategy for AD. : Yasukawa et al. demonstrate that BRI2 and BRI3, physiological inhibitors of Aβ production and aggregation, are substrates of NRBP1-ubiquitin ligase. In the presence of TSC22D3 and TSC22D4, a dimer of the substrate receptor NRBP1 assembles into a functional Cul2- and Cul4A-containing heterodimeric CRL through overlapping BC-box and cryptic H-box motifs on NRBP1. Keywords: E3 ubiquitin ligase, CRL, Cullin, ubiquitination, NRBP1, Alzheimer’s disease, amyloid β, amyloid-β precursor protein/APP, BRI2/ITM2B, BRI3/ITM2C |
| first_indexed | 2024-12-20T01:12:24Z |
| format | Article |
| id | doaj.art-25b40895c06f4376bab27bd94b941627 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-20T01:12:24Z |
| publishDate | 2020-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-25b40895c06f4376bab27bd94b9416272022-12-21T19:58:40ZengElsevierCell Reports2211-12472020-03-01301034783491.e6NRBP1-Containing CRL2/CRL4A Regulates Amyloid β Production by Targeting BRI2 and BRI3 for DegradationTakashi Yasukawa0Aya Tsutsui1Chieri Tomomori-Sato2Shigeo Sato3Anita Saraf4Michael P. Washburn5Laurence Florens6Tohru Terada7Kentaro Shimizu8Ronald C. Conaway9Joan W. Conaway10Teijiro Aso11Department of Functional Genomics, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi 783-8505, JapanDepartment of Functional Genomics, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi 783-8505, JapanStowers Institute for Medical Research, Kansas City, MO 64110, USAStowers Institute for Medical Research, Kansas City, MO 64110, USAStowers Institute for Medical Research, Kansas City, MO 64110, USAStowers Institute for Medical Research, Kansas City, MO 64110, USA; Department of Pathology and Laboratory Medicine, Kansas University Medical Center, Kansas City, KS 66160, USAStowers Institute for Medical Research, Kansas City, MO 64110, USAInterfaculty Initiative in Information Studies, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Agricultural Bioinformatics Research Unit, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, JapanAgricultural Bioinformatics Research Unit, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan; Department of Biotechnology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, JapanStowers Institute for Medical Research, Kansas City, MO 64110, USA; Department of Biochemistry and Molecular Biology, Kansas University Medical Center, Kansas City, KS 66160, USAStowers Institute for Medical Research, Kansas City, MO 64110, USA; Department of Biochemistry and Molecular Biology, Kansas University Medical Center, Kansas City, KS 66160, USADepartment of Functional Genomics, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi 783-8505, Japan; Corresponding authorSummary: Alzheimer’s disease (AD) is a progressive neurodegenerative disease caused by accumulations of Aβ peptides. Production and fibrillation of Aβ are downregulated by BRI2 and BRI3, which are physiological inhibitors of amyloid precursor protein (APP) processing and Aβ oligomerization. Here, we identify nuclear receptor binding protein 1 (NRBP1) as a substrate receptor of a Cullin-RING ubiquitin ligase (CRL) that targets BRI2 and BRI3 for degradation. Moreover, we demonstrate that (1) dimerized NRBP1 assembles into a functional Cul2- and Cul4A-containing heterodimeric CRL through its BC-box and an overlapping cryptic H-box, (2) both Cul2 and Cul4A contribute to NRBP1 CRL function, and (3) formation of the NRBP1 heterodimeric CRL is strongly enhanced by chaperone-like function of TSC22D3 and TSC22D4. NRBP1 knockdown in neuronal cells results in an increase in the abundance of BRI2 and BRI3 and significantly reduces Aβ production. Thus, disrupting interactions between NRBP1 and its substrates BRI2 and BRI3 may provide a useful therapeutic strategy for AD. : Yasukawa et al. demonstrate that BRI2 and BRI3, physiological inhibitors of Aβ production and aggregation, are substrates of NRBP1-ubiquitin ligase. In the presence of TSC22D3 and TSC22D4, a dimer of the substrate receptor NRBP1 assembles into a functional Cul2- and Cul4A-containing heterodimeric CRL through overlapping BC-box and cryptic H-box motifs on NRBP1. Keywords: E3 ubiquitin ligase, CRL, Cullin, ubiquitination, NRBP1, Alzheimer’s disease, amyloid β, amyloid-β precursor protein/APP, BRI2/ITM2B, BRI3/ITM2Chttp://www.sciencedirect.com/science/article/pii/S2211124720302278 |
| spellingShingle | Takashi Yasukawa Aya Tsutsui Chieri Tomomori-Sato Shigeo Sato Anita Saraf Michael P. Washburn Laurence Florens Tohru Terada Kentaro Shimizu Ronald C. Conaway Joan W. Conaway Teijiro Aso NRBP1-Containing CRL2/CRL4A Regulates Amyloid β Production by Targeting BRI2 and BRI3 for Degradation Cell Reports |
| title | NRBP1-Containing CRL2/CRL4A Regulates Amyloid β Production by Targeting BRI2 and BRI3 for Degradation |
| title_full | NRBP1-Containing CRL2/CRL4A Regulates Amyloid β Production by Targeting BRI2 and BRI3 for Degradation |
| title_fullStr | NRBP1-Containing CRL2/CRL4A Regulates Amyloid β Production by Targeting BRI2 and BRI3 for Degradation |
| title_full_unstemmed | NRBP1-Containing CRL2/CRL4A Regulates Amyloid β Production by Targeting BRI2 and BRI3 for Degradation |
| title_short | NRBP1-Containing CRL2/CRL4A Regulates Amyloid β Production by Targeting BRI2 and BRI3 for Degradation |
| title_sort | nrbp1 containing crl2 crl4a regulates amyloid β production by targeting bri2 and bri3 for degradation |
| url | http://www.sciencedirect.com/science/article/pii/S2211124720302278 |
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