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 and Paul N. Moynagh ()
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Fiachra Humphries: National University of Ireland Maynooth, Maynooth
Ronan Bergin: National University of Ireland Maynooth, Maynooth
Ruaidhri Jackson: National University of Ireland Maynooth, Maynooth
Nezira Delagic: National University of Ireland Maynooth, Maynooth
Bingwei Wang: National University of Ireland Maynooth, Maynooth
Shuo Yang: National University of Ireland Maynooth, Maynooth
Alice V. Dubois: Queen’s University Belfast
Rebecca J. Ingram: Queen’s University Belfast
Paul N. Moynagh: National University of Ireland Maynooth, Maynooth

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03669-z

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