Journal
JOURNAL OF IMMUNOLOGY
Volume 201, Issue 8, Pages 2256-2263Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1701446
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Funding
- KAKENHI
- Takeda Science Foundation
- Institute for Fermentation Osaka
- Mitsubishi Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Suzuken Memorial Foundation
- Japan Prize Foundation
- Ono Medical Research Foundation
- Kanzawa Medical Research Foundation
- Kishimoto Foundation
- Nagao Takeshi Research Foundation
- Japan Multiple Sclerosis Society
- Kanae Foundation
- Uehara Memorial Foundation
- Japan Brain Foundation
- Kao Foundation for Arts and Sciences
- Tokyo Medical Research Foundation
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We recently reported that NF-kappa B-mediated inflammation caused by breakpoint cluster region (BCR) is dependent on the a subunit of casein kinase II (CK2 alpha) 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-CK2 alpha-p65 complex to induce NF-kappa B activation. Indeed, Psen1 deficiency in mouse endothelial cells showed a significant reduction of NF-kappa B p65 recruitment to target gene promoters. Conversely, Psen1 overexpression enhanced reporter activation under NF-kappa B responsive elements and IL-6 promoter. Furthermore, the transcription of NF-kappa B target genes was not inhibited by a gamma-secretase inhibitor, suggesting that Psen1 regulates NF-kappa B activation in a manner independent of gamma-secretase activity. Mechanistically, Psen1 associated with the BCR-CK2 alpha 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-CK2 alpha-p65 complex was perturbed in the absence of Psen1. These results suggest that Psen1 functions as a scaffold of the BCR-CK2 alpha-p65 complex and that this signaling cascade could be a novel therapeutic target for various chronic inflammation conditions, including those in Alzheimer disease.
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