Presenilin 1 Regulates NF-κB Activation via Association with Breakpoint Cluster Region and Casein Kinase II

Abstract

We recently reported that NF-κB-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 γ-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-κB activation. Indeed, Psen1 deficiency in mouse endothelial cells showed a significant reduction of NF-κB p65 recruitment to target gene promoters. Conversely, Psen1 overexpression enhanced reporter activation under NF-κB responsive elements and IL-6 promoter. Furthermore, the transcription of NF-κB target genes was not inhibited by a γ-secretase inhibitor, suggesting that Psen1 regulates NF-κB activation in a manner independent of γ-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.

Role of Chondrocytes in the Development of Rheumatoid Arthritis Via Transmembrane Protein 147–MediatedNF‐κB Activation

“…In cytokine-induced RA models, 100 ng of human IL-6 (Toray Industries), 100 ng of mouse IL-17A (R&D Systems), or saline was injected into the ankle joints of F759 mice, as described previously (24). In some experiments, lentivirus particles carrying shRNA specific for TMEM147 (Sigma-Aldrich) or a scrambled sequence (Sigma-Aldrich) were injected into the ankle joints of mice (12,17,19,(24)(25)(26)(27). Anti-TMEM147 antibodies (Sigma-Aldrich) were injected into the ankle joints of mice at a dosage of 2 μg per day.…”

Increased urinary exosomal SYT17 levels in chronic active antibody-mediated rejection after kidney transplantation via the IL-6 amplifier

“…We have reported that the IL-6 amplifier is triggered by the simultaneous activation of two transcriptional factors, NFκB and STAT3, in non-immune cells, and that this activation is associated with various inflammatory pathologies (7,8,(11)(12)(13)(14)(15)(16)(17)(18)(19). The co-activation of NFκB and STAT3 Takada et al p. 14 synergistically promotes the production of various NFκB-target genes including IL-6 (7,8,(11)(12)(13)(14)(15)(16)(17)(18)(19).…”

“…The co-activation of NFκB and STAT3 enhances NFκB signaling to synergistically promote the production of various NFκB-driven inflammatory mediators including IL-6, chemokines and growth factors, and induce chronic inflammation in the affected tissues (8)(9)(10). Inhibition of the IL-6 amplifier significantly improves pathological outcomes in mouse disease models including allogenic transplantation rejection, multiple sclerosis, dermatitis, uveoretinitis and rheumatoid arthritis (7,8,(11)(12)(13)(14)(15)(16)(17)(18)(19). Consistently, its activation is observed in human allogeneic lung transplantation with chronic rejection phenotypes, and target molecules of the IL-6 amplifier are elevated in patients with inflammatory diseases such as atherosclerosis, multiple sclerosis, lung transplant rejection, keloid, and rheumatoid arthritis (7,13,20).…”

Cellular Specificity of NF-κB Function in the Nervous System

“…Promoter analysis and functional studies link expression of each of these genes to regulation by NF-κB (82–85). In some cases, products from AD-associated genes, such as presenilin 1, have also been shown to mediate reciprocal activation of NF-κB (RelA/p65 containing dimers) in putative pro-inflammatory cascades (86).…”