Yasukawa T, Tsutsui A, Tomomori-Sato C, Sato S, Saraf A, Washburn MP, Florens L, Terada T, Shimizu K, Conaway RC, Conaway JW, Aso T

Alzheimer's disease (AD) is a progressive neurodegenerative disease caused by accumulations of A? peptides. Production and fibrillation of A? are downregulated by BRI2 and BRI3, which are physiological inhibitors of amyloid precursor protein (APP) processing and A? oligomerization. Here, we identify nuclear receptor binding protein 1 (NRBP1) as a substrate ...

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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 A? production. Thus, disrupting interactions between NRBP1 and its substrates BRI2 and BRI3 may provide a useful therapeutic strategy for AD.

Date: Dec. 10, 2019

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