Humphries, Fiachra and Bergin, Ronan and Jackson, Ruaidhri and Delagic, Nezira and Wang, Bingwei and Yang, Shuo and Dubois, Alice V. and Ingram, Rebecca J. and Moynagh, Paul N. (2018) The E3 ubiquitin ligase Pellino2 mediates priming of the NLRP3 inflammasome. Nature Communications, 9 (1560). ISSN 2041-1723

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Abstract

The NLRP3 inflammasome has an important function in inflammation by promoting the processing of pro-IL-1β and pro-IL-18 to their mature bioactive forms, and by inducing cell death via pyroptosis. Here we show a critical function of the E3 ubiquitin ligase Pellino2 in facilitating activation of the NLRP3 inflammasome. Pellino2-deficient mice and myeloid cells have impaired activation of NLRP3 in response to toll-like receptor priming, NLRP3 stimuli and bacterial challenge. These functions of Pellino2 in the NLRP3 pathway are dependent on Pellino2 FHA and RING-like domains, with Pellino2 promoting the ubiquitination of NLRP3 during the priming phase of activation. We also identify a negative function of IRAK1 in the NLRP3 inflammasome, and describe a counter-regulatory relationship between IRAK1 and Pellino2. Our findings reveal a Pellino2-mediated regulatory signaling system that controls activation of the NLRP3 inflammasome.

Item Type:	Article
Additional Information:	© The Author(s) 2018. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/.
Keywords:	E3 ubiquitin ligase Pellino2; priming; NLRP3 inflammasome;
Academic Unit:	Faculty of Science and Engineering > Biology
Item ID:	11029
Identification Number:	https://doi.org/10.1038/s41467-018-03669-z
Depositing User:	Professor Paul Moynagh
Date Deposited:	10 Sep 2019 14:03
Journal or Publication Title:	Nature Communications
Publisher:	Nature Publshing Group
Refereed:	Yes
Funders:	Science Foundation Ireland (SFI)
URI:	https://www.nature.com/
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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