The role of PLK1 in NLRP3 inflammasome activation

The NLRP3 inflammasome is a heteroprotein complex that assembles in response to a variety of DAMPs (Damage-Associated Molecular Patterns) and PAMPs (Pathogen-Associated Molecular Patterns). Activation of the NLRP3 inflammasome leads to pro-inflammatory cytokines (IL-1 and IL-18) release and pyroptosis, an inflammasome-specific form of cell death. The kinase PLK1 plays an important and well-characterised role in mitosis, but the function of this protein in interphase has been poorly studied so far. I showed that mitosis and NLRP3 inflammasome activation are mutually exclusive events in murine BMDMs (Bone Marrow Derived Macrophages) and that PLK1 is an important regulator of NLRP3 inflammasome activation. Using two different potent and specific PLK1 inhibitors, I demonstrated that PLK1 inhibition impairs the NLRP3 inflammasome pathway. Accordingly, PLK1 levels are tightly regulated over the course of NLRP3 inflammasome activation. I generated multiple in vitro PLK1 depletion models in macrophages and combined them with the described chemical inhibition approach to show that PLK1-mediated regulation of the NLRP3 inflammasome occurs through a microtubule-dependent mechanism. During NLRP3 inflammasome activation, PLK1 promotes structural rearrangements of γ-Tubulin, with some similarities to the function of this protein in mitosis. I confirmed that PLK1 is an important player in the innate immune response in two different in vivo murine models of inflammation. Taken together, my results uncover an unprecedented moonlighting role for PLK1. As aberrant activation of the NLRP3 inflammasome is a hallmark of multiple inflammatory diseases, my findings suggest that pharmaceutical inhibition of PLK1 might be a promising therapeutic strategy to target excessive NLRP3 activation.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2020

Author dc:creator

• Baldrighi, Marta

Advisor dc:contributor.advisor

• Li, Xuan

• Inflammation
• NLRP3
• Inflammasome
• PLK1
• subcellular localisation
• small molecule inhibitor
• macrophage

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/4b40b3a7-3702-477d-a491-9f485abe0858/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

Author Identifier

0000-0002-2371-268X
0000-0002-0754-3011

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/318227