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Browsing Open Theses and Dissertations by Subject "17-DMAG"
An 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.