Mechanisms Governing NF-κB Regulation by the Anti-Inflammatory Protein A20

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dc.contributor.advisorChen, Zhijian J.en
dc.contributor.committeeMemberCobb, Melanie H.en
dc.contributor.committeeMemberSternweis, Paul C.en
dc.contributor.committeeMemberYarovinsky, Felixen
dc.creatorSkaug, Brianen
dc.date.accessioned2015-07-27T16:02:14Z
dc.date.created2013-05
dc.date.issued2013-05-31
dc.date.submittedMay 2013
dc.description.abstractA20 is a potent anti-inflammatory protein that inhibits NF-ΚB, and A20 dysfunction is associated with autoimmunity and B-cell lymphoma. A20 harbors a deubiquitination enzyme domain and can employ multiple mechanisms to antagonize ubiquitination upstream of NEMO, a regulatory subunit of the IκB kinase complex (IKK). However, direct evidence of IKK inhibition by A20 is lacking, and the inhibitory mechanism remains poorly understood. Here we show that A20 can directly impair IKK activation without deubiquitination or impairment of ubiquitination enzymes. We find that polyubiquitin binding by A20, which is largely dependent on A20’s 7th zinc finger motif (ZnF7), induces specific binding to NEMO. Remarkably, this ubiquitin-induced recruitment of A20 to NEMO is sufficient to block IKK phosphorylation by its upstream kinase TAK1. Our results suggest a novel mechanism of IKK inhibition and a means by which polyubiquitin chains can specify a signaling outcome.en
dc.format.mimetypeapplication/pdfen
dc.identifier.oclc914484640
dc.identifier.urihttps://hdl.handle.net/2152.5/1706
dc.language.isoenen
dc.subjectI-kappa B Kinaseen
dc.subjectInflammationen
dc.subjectIntracellular Signaling Peptides and Proteinsen
dc.subjectNF-kappa Ben
dc.titleMechanisms Governing NF-κB Regulation by the Anti-Inflammatory Protein A20en
dc.title.alternativeMechanisms governing NF-[kappa]B regulation by the anti-inflammatory protein A20en
dc.typeThesisen
dc.type.materialTexten
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineCell Regulationen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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