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    • Boulares group has demonstrated that

    2019-07-22

    Boulares group [82] has demonstrated that the NF-κB1/p50 NF-κB, a family member of type I NF-κB, is an excellent substrate for DNA-PK, which-dependent phosphorylation of NF-κB1 at serine 20 appears to enhance its binding to DNA as either a homodimer or a heterodimer with p65 NF-κB and the ability of NF-κB1 to drive the transcription of a number of additional NF-κB1-dependent genes, such as VCAM-1. Mutation of serine 20 completely eliminated phosphorylation of NF-κB1 by DNA-PK, and re-establishing wild type p50 NF-κB1, but not its serine 20/alanine mutant, in NF-κB1−/− fibroblasts reversed VCAM-1 expression after TNF treatment, demonstrating the importance of the serine 20 phosphorylation site in the induction of VCAM-1 expression. Furthermore, DNA-PK is also involved in the proinflammatory response initiated by CD158d signals. CD158d, also known as the killer cell immunoglobulin like receptor 2 DL4 (KIR2DL4), is a member of the killer cell immunoglobulin (Ig)-like receptor (KIR) family and is found in all natural killer (NK) STA-21 and in some T cells. Unlike other KIRs, CD158d resides in Rab5-containing early endosomes and signals from this intracellular location [83]. Soluble ligand such as soluble HLA-G or an antigen-binding fragment (Fab) of an antibody to CD158d, is endocytosed by CD158d and induces a unique proinflammatory and proangiogenic response in NK cells [83]. Activation of resting human NK cells by CD158d stimulates the secretion of cytokines, but not cytotoxicity [84], [85]. The transcriptional response to CD158d signals includes the expression of cytokines, such as IL-1b, IL-6, tumor necrosis factor-a (TNF-a), and IL-23 and chemokines, such as IL-8, macrophage inflammatory protein-3a (MIP-3a), MIP-1d, and MIP-1a. Long group reported [86] that this CD158d-initiated proinflammatory response is mediated by the cascade activation of DNA-PKcs, Akt and NF-kB. In response to soluble agonist antibody or soluble HLA-G, CD158d interacts with DNA-PKcs in Rab5-containing endosomes. The CD158d signaling recruits Akt to endosomes and stimulates the DNA-PKcs-dependent phosphorylation of Akt at Ser473. In turn, Akt leads to the activation of NF-kB to trigger a proinflammatory response [87], [88], [89], [90]. However, in the proinflammatory response, both Ku subunits were not present in the CD158d-associated proteins identified by MS [86], which was consistent with the in vitro study data from the other independent group [91]. Since DNA-PK activates Akt through the phosphorylation of same residue of Ser473 in response to ionizing radiation [90], [92], [93], this phosphorylation may trigger the proinflammatory response, which may explain, at least partially, how ionizing radiation initiates inflammatory response in tissue.
    The important role of DNA-PK in metabolic gene regulation To meet the constant energy requirement in the face of highly variable food supply, mammals employ intricate and precise mechanisms for energy storage. When total energy intake is in excess of energy expenditure (such as after a meal), excess carbohydrates are converted to fatty acids (de novo lipogenesis). Excess fatty acids are then converted to triacylglycerols to be stored in adipose tissue and released as oxidative fuels for other tissues during times of energy need (such as fasting and exercise). In sustaining the balance between energy excess and energy deficiency, the process of lipogenesis is tightly controlled by nutritional and hormonal conditions [94]. Thus, enzymes involved in fatty acid and fat synthesis are tightly and coordinately regulated during fasting/feeding: The expression of the lipogenic enzymes is very low in fasting due to the increase in glucagon/cAMP levels. Conversely, in the fed condition, especially after a high carbohydrate meal, the expression of these enzymes is drastically upregulated and accompanied by an increase in insulin secretion [94], [95], [96]. Fatty acid synthase (FAS), a central lipogenic enzyme, plays a crucial role in de novo lipogenesis by catalyzing all of the seven reactions involved in fatty acid synthesis.