ATM REGULATES THE NF-kB PATHWAY VIA RELA SER 276 PHOSPHORYLATION

dc.contributor.advisorChoudhary, Sanjeev
dc.contributor.committeeMemberBrasier , Allan
dc.contributor.committeeMemberBoldogh, Istvan
dc.contributor.committeeMemberHazra, Tapas
dc.contributor.committeeMemberWu, Zhaohui
dc.creatorFang, Ling
dc.date.accessioned2019-03-13T20:46:51Z
dc.date.available2019-03-13T20:46:51Z
dc.date.created2014-08
dc.date.submittedAugust 2014
dc.date.updated2019-03-13T20:46:51Z
dc.description.abstractAtaxia-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-and RSV- 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 IKKr-ubiquitin association and complex formation with ATM for nuclear export. Activated cytoplasmic ATM is involved in the selective recruitment of the E3-ubiquitin ligase b-TrCP to phospho-IkBa proteosomal degradation. Importantly, ATM binds and activates the catalytic subunit of protein kinase A (PKAc), a 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-kB-dependent immediate early cytokine genes, in ATM knockdown cells. We conclude that ATM is a nuclear damage-response signal modulator of TNF-induced NF-kB activation that plays a key scaffolding role in IkBa degradation and RelA Ser 276 phosphorylation. In the antiviral response pathway, we observed RSV infection activates ATM and ATM is also required for RSV induced RelA Ser 276 phosphorylation. We further demonstrated that IRF7 gene expression is pRelA Ser 276 dependent and IRF7 is a essential regulator of RIG-I gene expression. Depletion of ATM results in an increased RSV proliferation and reduced IFN and ISG gene expression, indicating the significance of resynthesized RIG-I regulated by IRF7. These results demonstrate a RSV- phospho-Ser 276 RelA-IRF7-RIG-I pathway mediated by ATM. Taken together, our study provides a mechanistic explanation of decreased innate immune response associated with A-T mutation.
dc.format.mimetypeapplication/pdf
dc.identifier.urihttps://hdl.handle.net/2152.3/11201
dc.subjectNF-kB ATM
dc.titleATM REGULATES THE NF-kB PATHWAY VIA RELA SER 276 PHOSPHORYLATION
dc.typeThesis
dc.type.materialtext
thesis.degree.departmentBiochemistry and Molecular Biology
thesis.degree.disciplineBiochemistry and Molecular Biology
thesis.degree.grantorThe University of Texas Medical Branch at Galveston
thesis.degree.levelDoctoral
thesis.degree.nameBiochemistry and Molecular Biology (Doctoral)

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