| First Author | Tanaka Y | Year | 2018 |
| Journal | J Immunol | Volume | 201 |
| Issue | 8 | Pages | 2256-2263 |
| PubMed ID | 30201812 | Mgi Jnum | J:266223 |
| Mgi Id | MGI:6203356 | Doi | 10.4049/jimmunol.1701446 |
| Citation | Tanaka Y, et al. (2018) Presenilin 1 Regulates NF-kappaB Activation via Association with Breakpoint Cluster Region and Casein Kinase II. J Immunol 201(8):2256-2263 |
| abstractText | We recently reported that NF-kappaB-mediated inflammation caused by breakpoint cluster region (BCR) is dependent on the alpha subunit of casein kinase II (CK2alpha) complex. In the current study, we demonstrate that presenilin 1 (Psen1), which is a catalytic component of the gamma-secretase complex and the mutations of which are known to cause familial Alzheimer disease, acts as a scaffold of the BCR-CK2alpha-p65 complex to induce NF-kappaB activation. Indeed, Psen1 deficiency in mouse endothelial cells showed a significant reduction of NF-kappaB p65 recruitment to target gene promoters. Conversely, Psen1 overexpression enhanced reporter activation under NF-kappaB responsive elements and IL-6 promoter. Furthermore, the transcription of NF-kappaB target genes was not inhibited by a gamma-secretase inhibitor, suggesting that Psen1 regulates NF-kappaB activation in a manner independent of gamma-secretase activity. Mechanistically, Psen1 associated with the BCR-CK2alpha complex, which is required for phosphorylation of p65 at serine 529. Consistently, TNF-alpha-induced phosphorylation of p65 at serine 529 was significantly decreased in Psen1-deficient cells. The association of the BCR-CK2alpha-p65 complex was perturbed in the absence of Psen1. These results suggest that Psen1 functions as a scaffold of the BCR-CK2alpha-p65 complex and that this signaling cascade could be a novel therapeutic target for various chronic inflammation conditions, including those in Alzheimer disease. |
