Phosphorylation of CBP by IKKα links intestinal homeostasis

Abstract CBP is a transcriptional coactivator participating in the regulation of DNA accessibility to transcription factors. Phosphorylation of human CBP by IKKα at serines 1382/1386 plays a critical role in regulating cell destiny via suppressing p53-mediated gene expression. We aimed to determine whether impaired phosphorylation of CBP is involved in the pathogenesis of disease. Hence, we designed and generated mutated serine 1383/1387 to alanine knockin mice (AA mice) to study whether they exhibit any phenotype alteration. AA mice showed an IBD-like phenotype with softer, looser and hemoccult stools and shorter colon length compared to the wild type mice. Increased p53 accompanied with apoptosis in colonic tissues of AA mice was demonstrated by IHC and TUNEL staining. In addition, male AA mice were more vulnerable to DSS-induced colitis with severe crypt loss and epithelial disruption. Elevated immune cells in mesenteric lymph nodes are also more prominent in AA mice with infiltration of neutrophil and macrophage. However, the differentiation of CD4+ T cells was not affected with Cbp mutation (AA) ex vivo. Colonic biopsies show that patients with ulcerative colitis have significantly lower phosphorylated CBP (Ser1382/1386) than healthy controls. Collectively, deficiency of NF-κB signaling in AA mice did not affect immune cells but modulated apoptosis of IECs. Our findings suggested that phosphorylation of CBP by IKKα might be a critical regulator to maintain intestinal homeostasis.