Presenilin 1 Regulates NF-{kappa}B Activation via Association with Breakpoint Cluster Region and Casein Kinase II [IMMUNE REGULATION]

We recently reported that NF-B–mediated inflammation caused by breakpoint cluster region (BCR) is dependent on the α subunit of casein kinase II (CK2α) complex. In the current study, we demonstrate that presenilin 1 (Psen1), which is a catalytic component of the -secretase complex and the mutations of which are known to cause familial Alzheimer disease, acts as a scaffold of the BCR–CK2α–p65 complex to induce NF-B activation. Indeed, Psen1 deficiency in mouse endothelial cells showed a significant reduction of NF-B p65 recruitment to target gene promoters. Conversely, Psen1 overexpression enhanced reporter activation under NF-B responsive elements and IL-6 promoter. Furthermore, the transcription of NF-B target genes was not inhibited by a -secretase inhibitor, suggesting that Psen1 regulates NF-B activation in a manner independent of -secretase activity. Mechanistically, Psen1 associated with the BCR–CK2α complex, which is required for phosphorylation of p65 at serine 529. Consistently, TNF-α–induced phosphorylation of p65 at serine 529 was significantly decreased in Psen1-deficient cells. The association of the BCR–CK2α–p65 complex was perturbed in the absence of Psen1. These results suggest that Psen1 functions as a scaffold of the BCR–CK2α–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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