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Cell Rep. 2020 Mar 10;30(10):3478-3491.e6. doi: 10.1016/j.celrep.2020.02.059.

NRBP1-Containing CRL2/CRL4A Regulates Amyloid β Production by Targeting BRI2 and BRI3 for Degradation.

Author information

1
Department of Functional Genomics, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi 783-8505, Japan.
2
Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
3
Stowers Institute for Medical Research, Kansas City, MO 64110, USA; Department of Pathology and Laboratory Medicine, Kansas University Medical Center, Kansas City, KS 66160, USA.
4
Interfaculty 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, Japan.
5
Agricultural 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, Japan.
6
Stowers Institute for Medical Research, Kansas City, MO 64110, USA; Department of Biochemistry and Molecular Biology, Kansas University Medical Center, Kansas City, KS 66160, USA.
7
Department of Functional Genomics, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi 783-8505, Japan. Electronic address: asot@kochi-u.ac.jp.

Abstract

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.

KEYWORDS:

Alzheimer’s disease; BRI2/ITM2B; BRI3/ITM2C; CRL; Cullin; E3 ubiquitin ligase; NRBP1; amyloid β; amyloid-β precursor protein/APP; ubiquitination

PMID:
32160551
DOI:
10.1016/j.celrep.2020.02.059
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Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

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