The PLK1 and NLRP3 interactome in NLRP3 inflammasome activation

Excessive activation of the NLRP3 inflammasome is involved in sterile inflammation in multiple chronic diseases such as atherosclerosis, gout, type 2 diabetes or Alzheimer’s disease. However, current treatment strategies using generic targeting of IL-1, the end product of multiple inflammasome pathways, can increase the rate of opportunistic infection. Identification of novel players specifically regulating the NLRP3 inflammasome could therefore lead to the development of new therapeutic strategies. Our unpublished work has identified the Polo-like kinase (PLK1) as a potential regulator of the NLRP3 inflammasome pathway. Using two different methods, I showed that PLK1 interacted with NLRP3 and that that interaction was enhanced during NLRP3 inflammasome activation. Moreover, I identified the potential domains responsible for this interaction. Protein-protein interactions regulate protein functionality of both PLK1 and NLRP3. Therefore, I set out to identify the PLK1 and NLRP3 interactome during NLRP3 inflammasome activation, which could indicate the underlying mechanism of how PLK1 regulates NLRP3. Using proximity-dependent biotin identification (BioID), a method based on fusion of a promiscuous biotin ligase to a protein of interest, I identified 553 and 645 proteins as potential new interacting partners of NLRP3 and PLK1 respectively during inflammasome activation. Using this method, I found that the centrosomal protein CEP192 interacted with NLRP3. I furthermore confirmed that CEP192 also interacted with PLK1 during NLRP3 inflammasome activation. Our data not only supports the regulatory role of PLK1 in the NLRP3 inflammasome pathway, but also reveals a potential mechanism via interaction of PLK1 with CEP192.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2021

Author dc:creator

• Doreth, Christian

Advisor dc:contributor.advisor

• Li, Xuan

• Inflammasome
• NLRP3
• PLK1
• Interactome

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/ae02b5cd-03c3-4852-b00e-0f4be2f59b55/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

Author Identifier

0000-0002-0754-3011

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/330677