The E3 ubiquitin ligase Pellino2 mediates priming of the NLRP3 inflammasome

Fiachra Humphries, Ronan Bergin, Ruaidhri Jackson, Nezira Delagic, Bingwei Wang, Shuo Yang, Alice V Dubois, Rebecca J Ingram, Paul N Moynagh

Research output: Contribution to journalArticlepeer-review

48 Citations (Scopus)
243 Downloads (Pure)

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 Savethe 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.

Original languageEnglish
Pages (from-to)1560
Number of pages17
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 19 Apr 2018

Keywords

  • Journal Article

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