Regulation of the NLRP3 Inflammasome by Cathepsin Z

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dc.contributor.advisorYates, Robin M.
dc.contributor.authorCampden, Rhiannon I
dc.contributor.committeememberHollenberg, Morley
dc.contributor.committeememberShi, Yan
dc.contributor.committeememberKhrisendath, Chadee
dc.contributor.committeememberAkkari, Leila
dc.dateFall Convocation
dc.date.accessioned2022-11-15T17:43:27Z
dc.date.embargolift2022-07-06
dc.date.issued2020-07-06
dc.description.abstractThe focus of this dissertation is on understanding how cathepsin Z is involved in the initiation of inflammation, and specifically, how cathepsin Z contributes to the production of interleukin (IL)-1? following NLRP3 inflammasome activation. IL-1? is a pro-inflammatory cytokine involved in the recruitment of immune cells and the polarization of TH17 cells. Activation of the NLRP3 inflammasome, which is a macromolecular complex composed of a receptor (NLRP3), an adaptor protein (ASC), and the protease caspase-1, leads to cleavage and release of IL-1?. Cathepsin Z contains dual functions as a C-terminal exopeptidase and an integrin-binding protein. Initially, we explored the involvement of cathepsin Z in the development of inflammation in a mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). We found that cathepsin Z is required for the recruitment of immune cells into the central nervous system (CNS). Here, we found cathepsin Z is involved in TH17 polarization due to reduced IL-1?, but not antigen processing, T cell activation nor T cell migration. This led us to investigate the mechanism through which cathepsin Z regulates IL-1? production. We found that extracellular cathepsin Z signals through the ?5 integrin following NLRP3 inflammasome activation. Furthermore, the function of cathepsin Z in this context was dependent on the integrin-binding domain of cathepsin Z and not its proteolytic activity. This reveals another mechanism of NLRP3 regulation through an endogenous extracellular protein that signals through integrins. Finally, we employed proteomic and degradomic approaches following NLRP3 inflammasome activation in the absence of NLRP3 to gain a deeper understanding of the proteins involved in NLRP3 inflammasome activation. In the absence of NLRP3, caspase-1 and IL-1? are degraded, while caspase-4 is stabilized. Further, ROS levels are lower following NLRP3 inflammasome activation with silica in the absence of NLRP3, and the expression of several mitochondrial proteins are deregulated, suggesting the importance of the mitochondria and ROS signalling in NLRP3 inflammasome activation. Collectively, this dissertation reveals a novel extracellular regulatory pathway of the NLRP3 inflammasome and further outlines the signalling function of cathepsin Z in inflammation. This dissertation also presents a dataset of proteins for investigation in NLRP3 inflammasome activation.
dc.identifier.citationCampden, R. I. (2020). Regulation of the NLRP3 Inflammasome by Cathepsin Z (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.
dc.identifier.urihttp://hdl.handle.net/1880/115493
dc.identifier.urihttps://dx.doi.org/10.11575/PRISM/40460
dc.language.isoenen
dc.language.isoEnglish
dc.publisher.facultyGraduate Studiesen
dc.publisher.facultyCumming School of Medicine
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
dc.subjectInflammasome
dc.subjectCathepsins
dc.subjectCathepsin Z
dc.subjectIntegrin
dc.subjectMultiple Sclerosis
dc.subjectExperimental Autoimmune Encephalomyelitis
dc.subjectInflammation
dc.subjectInterleukin-1
dc.subjectTh17 cells
dc.subjectcaspase-1
dc.subjectSilicosis
dc.subjectMass Spectrometry
dc.subjectTerminal amine isotopic labeling of substrates
dc.subject.classificationBiology--Molecular
dc.subject.classificationBiology--Cell
dc.titleRegulation of the NLRP3 Inflammasome by Cathepsin Z
dc.typedoctoral thesis
thesis.degree.disciplineBiological Sciences
thesis.degree.grantorUniversity of Calgaryen
thesis.degree.grantorUniversity of Calgary
thesis.degree.nameDoctor of Philosophy (PhD)
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