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.
Highlights
Alzheimer’s disease (AD) is characterized by accumulations of insoluble deposits of Ab peptides in the extracellular space of the brain parenchyma (Haass and Selkoe, 2007)
In an alternative non-amyloidogenic proteolytic pathway, amyloid precursor protein (APP) is first cleaved in the middle of the Ab region by a-secretase, shedding soluble APPa and generating a truncated APP CTF (a-CTF), which lacks the amino-terminal portion of the Ab domain. a-CTF is cleaved by g-secretase into two peptides, APP intracellular domain (AICD) and a truncated peptide p3, which is apparently non-pathogenic (Haass et al, 2012)
Cycloheximide chase analysis demonstrated that TSC22D3 had little effect on the stability of nuclear receptor binding protein 1 (NRBP1), TSC22D4 markedly increased its stability, while the stability of Cul2 was increased when both TSC22D3 and TSC22D4 were co-expressed (Figure 1C). These findings suggest that TSC22D3 and TSC22D4 appear to serve as molecular chaperones to promote NRBP1-Cul2 assembly by different mechanisms
Summary
Alzheimer’s disease (AD) is characterized by accumulations of insoluble deposits of Ab peptides in the extracellular space of the brain parenchyma (Haass and Selkoe, 2007). Type II transmembrane proteins BRI2 and BRI3 have been reported to negatively regulate Ab production by binding to APP and inhibiting its processing by secretases. Both proteins mask the cleavage sites of a- and b-secretase on APP, while BRI2 masks the g-secretase docking site on b-CTF (Fotinopoulou et al, 2005; Matsuda et al, 2005, 2009). Disease-causing mutations at or near the stop codon result in the production of C-terminally extended, 277 amino acid mutant BRI2 proteins, which are cleaved at the normal protease processing site to generate mature BRI2 and distinct 34 amino acid amyloidogenic peptides (ABri in FBD and ADan in FDD), which accumulate in the brain of affected patients (Vidal et al, 1999, 2000). Mutations in the BRI2 gene render mutant BRI2 protein unstable, such that it is mostly degraded (Tamayev et al, 2010a, 2010b)
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