Abstract
Ataxia-telangiectasia mutated (ATM), a member of the phosphatidylinositol 3 kinase-like kinase family, is a master regulator of the double strand DNA break-repair pathway after genotoxic stress. Here, we found ATM serves as an essential regulator of TNF-induced NF-kB pathway. We observed that TNF exposure of cells rapidly induced DNA double strand breaks and activates ATM. TNF-induced ROS promote nuclear IKKγ association with ubiquitin and its complex formation with ATM for nuclear export. Activated cytoplasmic ATM is involved in the selective recruitment of the E3-ubiquitin ligase β-TrCP to phospho-IκBα proteosomal degradation. Importantly, ATM binds and activates the catalytic subunit of protein kinase A (PKAc), ribosmal S6 kinase that controls RelA Ser 276 phosphorylation. In ATM knockdown cells, TNF-induced RelA Ser 276 phosphorylation is significantly decreased. We further observed decreased binding and recruitment of the transcriptional elongation complex containing cyclin dependent kinase-9 (CDK9; a kinase necessary for triggering transcriptional elongation) to promoters of NF-κB-dependent immediate-early cytokine genes, in ATM knockdown cells. We conclude that ATM is a nuclear damage-response signal modulator of TNF-induced NF-κB activation that plays a key scaffolding role in IκBα degradation and RelA Ser 276 phosphorylation. Our study provides a mechanistic explanation of decreased innate immune response associated with A-T mutation.
Highlights
Nuclear factor-B (NF-B) is a major transcription factor that plays a central role in triggering the innate and adaptive immune response [1,2]
Ataxia-telangiectasia mutated (ATM) activation has been reported to be coupled with nuclear export in the double-strand breaks (DSBs)-induced DNA repair pathway [8]
Elevated ROS and 8-oxoG formation is usually associated with ssDNA breaks, we evaluated the possibility whether TNF treatment is sufficient to induce DNA double strand breaks (DSBs) and provide a potential mechanism of TNFinduced ATM activation and nuclear export
Summary
Nuclear factor-B (NF-B) is a major transcription factor that plays a central role in triggering the innate and adaptive immune response [1,2]. The central mechanism of NF-B regulation is the signal dependent posttranslational modifications of the IB kinase (IKK) complex leading to phosphorylation and subsequent proteosomal degradation of a family of cytoplasmic NF-B inhibitors, the IBs [4]. This process releases the sequestered, inactive RelA·p50 heterodimer. The fully activated RelA complex mediates phosphorylation of RNA polymerase II leading to transcriptional elongation and induction of gene expression of a subset of immediate-early cytokine genes [6] In this manner, a cell transduces external environmental signaling into regulated patterns of gene expression
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