NRBP1-Containing CRL2/CRL4A Regulates Amyloid β Production by Targeting BRI2 and BRI3 for Degradation
NRBP1-Containing CRL2/CRL4A Regulates Amyloid β Production by Targeting BRI2 and BRI3 for Degradation
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DOI：
10.1016/j.celrep.2020.02.059
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发表时间：
2020-03-10
期刊：
影响因子：
8.8
通讯作者：
Aso, Teijiro
中科院分区：
文献类型：
--
作者：
Yasukawa, Takashi;Tsutsui, Aya;Aso, Teijiro
阿尔茨海默病（Alzheimer's disease，AD）是一种由A β肽积累引起的进行性神经退行性疾病。A β的产生和原纤化被BRI 2和BRI 3下调，BRI 2和BRI 3是淀粉样前体蛋白（APP）加工和A β寡聚化的生理抑制剂。在这里，我们确定核受体结合蛋白1（NRBP 1）作为Cullin-RING泛素连接酶（CRL）的底物受体，靶向BRI 2和BRI 3降解。此外，我们证明：（1）二聚化NRBP 1通过其BC盒和重叠的隐蔽H盒组装成功能性Cul 2和Cul 4A异二聚体CRL，（2）Cul 2和Cul 4A都有助于NRBP 1 CRL功能，（3）TSC 22 D3和TSC 22 D4的伴侣样功能强烈增强了NRBP 1异二聚体CRL的形成。神经元细胞中的NRBP 1敲低导致BRI 2和BRI 3丰度增加，并显著降低A β产生。因此，破坏NRBP 1与其底物BRI 2和BRI 3之间的相互作用可能为AD提供有用的治疗策略。
Alzheimer's disease (AD) is a progressive neurode-generative disease caused by accumulations of A beta peptides. Production and fibrillation of A beta are downregulated by BRI2 and BRI3, which are physiological inhibitors of amyloid precursor protein (APP) processing and A beta 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 A beta production. Thus, disrupting interactions between NRBP1 and its substrates BRI2 and BRI3 may provide a useful therapeutic strategy for AD.