Hsp90 Regulates the NLRP3 Inflammasome via the NF-kB Signaling Pathway

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dc.contributor.advisorBeck, Paul
dc.contributor.authorSparksman, Steven
dc.contributor.committeememberMuruve, Daniel
dc.contributor.committeememberMacDonald, Justin
dc.contributor.committeememberMcKay, Derek
dc.contributor.committeememberBraun, Janice
dc.date2020-06
dc.date.accessioned2020-04-20T16:05:29Z
dc.date.available2020-04-20T16:05:29Z
dc.date.issued2020-04-17
dc.description.abstractAn over-reactive inflammatory response can lead to chronic inflammation and auto-immune disorders such as Crohn’s disease, ulcerative colitis or cancer. At the heart of the host’s inflammatory response is an immune cell intracellular sensor protein known as NLRP3 that regulates the cellular response to a wide range of PAMPS/DAMPS. NLRP3 has been characterized primarily as an inflammasome-forming protein in response to infection and injury. The inflammasome regulates IL-1β and IL-18 maturation leading to their subsequent secretion from the immune cell. Secretion of these cytokines recruits other immune cells and factors that leads to the resolution of the initiating infection or injury. Hsp90, with its co-chaperone SGT1, was shown to be required for NLRP3 inflammasome activation via a direct protein-protein interaction. An Hsp90-SGT1 interaction was suggested to stabilize NLRP3 prior to inflammasome activation allowing the sensing of PAMPS/DAMPS; however, the mechanism, timing and sequence of events of this interaction have yet to be shown experimentally. Thus, the central hypothesis of this thesis is that Hsp90 regulates the activation of the NLRP3 inflammasome by stabilizing NLRP3 via direct protein-protein interactions. Treatment with DMAG, an Hsp90 inhibitor, blocked canonical NLRP3 function in differentiated THP-1 immune cells. However, we found no evidence that Hsp90-SGT1 was involved in protein-protein interactions with NLRP3. Instead, experiments revealed that DMAG attenuated IL1β gene transcription but did not interfere with translocation of the transcription factor, NF-kB to the nucleus. This suggests Hsp90 regulates the NLRP3 inflammasome by regulating transcription of NLRP3 inflammasome component genes. This project has revealed new insights for Hsp90 in the inflammatory response and suggests Hsp90 as a credible target for chronic inflammatory disorders.en_US
dc.identifier.citationSparksman, S. (2020). Hsp90 Regulates the NLRP3 Inflammasome via the NF-kB Signaling Pathway (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/37689
dc.identifier.urihttp://hdl.handle.net/1880/111814
dc.language.isoengen_US
dc.publisher.facultyCumming School of Medicineen_US
dc.publisher.institutionUniversity of Calgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.en_US
dc.subjectDMAGen_US
dc.subject17-DMAGen_US
dc.subjectHsp90en_US
dc.subjectSGT1en_US
dc.subjectNLRP3en_US
dc.subjectC. diffen_US
dc.subjectCo-IPen_US
dc.subjectAGK2en_US
dc.subjectClostridium difficileen_US
dc.subjectHEK293en_US
dc.subjectHEK293Ten_US
dc.subjectLPSen_US
dc.subjectLipopolysaccharideen_US
dc.subjectNALP3en_US
dc.subjectPLAen_US
dc.subjectImmunofluorescenceen_US
dc.subjectProximity Ligation Assayen_US
dc.subjectNigericinen_US
dc.subjectPMAen_US
dc.subjectPhorbol 12-Myristate 13-Acetateen_US
dc.subjectSIRT2en_US
dc.subjectTHP-1en_US
dc.subjectTHP1en_US
dc.subjectTcdAen_US
dc.subjectTcdBen_US
dc.subjectMMP9en_US
dc.subjectZVADen_US
dc.subjectZ-VAD-fmken_US
dc.subjectInflammasomeen_US
dc.subjectCytokineen_US
dc.subjectFractionationen_US
dc.subjectIL-1βen_US
dc.subjectIκBαen_US
dc.subjectNF-κBen_US
dc.subjectTGF-βen_US
dc.subject.classificationEducation--Sciencesen_US
dc.subject.classificationBiology--Cellen_US
dc.subject.classificationMicrobiologyen_US
dc.subject.classificationBiology--Molecularen_US
dc.subject.classificationBiophysics--Medicalen_US
dc.subject.classificationImmunologyen_US
dc.subject.classificationBiochemistryen_US
dc.titleHsp90 Regulates the NLRP3 Inflammasome via the NF-kB Signaling Pathwayen_US
dc.typemaster thesisen_US
thesis.degree.disciplineMedicine – Gastrointestinal Sciencesen_US
thesis.degree.grantorUniversity of Calgaryen_US
thesis.degree.nameMaster of Science (MSc)en_US
ucalgary.item.requestcopytrueen_US
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