NRBP1-Containing CRL2/CRL4A Regulates Amyloid β Production by Targeting BRI2 and BRI3 for Degradation
Year: 2020
Type: article
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.
Source: Cell Reports
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,200
Awards: Role of transcription factor Elongin A with E3 activity in mouse neural development, G3560533418, Identification of Elongin A target genes and clarification of the mechanisms governing conversion of the Elongin complex from its elongation factor to its ubiquitin ligase form, Basic research for the development of therapeutic drugs for Alzheimer's disease targeting a novel ubiquitin ligase, In vivo role of transcriptional elongation/ubiquitin ligase factor Elongin, Basic study for development of novel anti-dementia drug which selectively targets BRI2/3-ubiquitin ligase, Identification of target genes of transcription elongation factor Elongin A and analysis of its regulation
OpenAlex ID: W3010718725