| First Author | Wang H | Year | 2013 |
| Journal | J Biol Chem | Volume | 288 |
| Issue | 37 | Pages | 26668-77 |
| PubMed ID | 23926111 | Mgi Jnum | J:205970 |
| Mgi Id | MGI:5547482 | Doi | 10.1074/jbc.M113.476689 |
| Citation | Wang H, et al. (2013) COPS5 (Jab1) protein increases beta site processing of amyloid precursor protein and amyloid beta peptide generation by stabilizing RanBP9 protein levels. J Biol Chem 288(37):26668-77 |
| abstractText | Increased processing of amyloid precursor protein (APP) and accumulation of neurotoxic amyloid beta peptide (Abeta) in the brain is central to the pathogenesis of Alzheimer's disease (AD). Therefore, the identification of molecules that regulate Abeta generation is crucial for future therapeutic approaches for AD. We demonstrated previously that RanBP9 regulates Abeta generation in a number of cell lines and primary neuronal cultures by forming tripartite protein complexes with APP, low-density lipoprotein-related protein, and BACE1, consequently leading to increased amyloid plaque burden in the brain. RanBP9 is a scaffold protein that exists and functions in multiprotein complexes. To identify other proteins that may bind RanBP9 and regulate Abeta levels, we used a two-hybrid analysis against a human brain cDNA library and identified COPS5 as a novel RanBP9-interacting protein. This interaction was confirmed by coimmunoprecipitation experiments in both neuronal and non-neuronal cells and mouse brain. Colocalization of COPS5 and RanBP9 in the same subcellular compartments further supported the interaction of both proteins. Furthermore, like RanBP9, COPS5 robustly increased Abeta generation, followed by increased soluble APP-beta (sAPP-beta) and decreased soluble-APP-alpha (sAPP-alpha) levels. Most importantly, down-regulation of COPS5 by siRNAs reduced Abeta generation, implying that endogenous COPS5 regulates Abeta generation. Finally, COPS5 levels were increased significantly in AD brains and APDeltaE9 transgenic mice, and overexpression of COPS5 strongly increased RanBP9 protein levels by increasing its half-life. Taken together, these results suggest that COPS5 increases Abeta generation by increasing RanBP9 levels. Thus, COPS5 is a novel RanBP9-binding protein that increases APP processing and Abeta generation by stabilizing RanBP9 protein levels. |
