Abstract

The NLRP3 inflammasome responds to infection and tissue damage, and rapidly escalates the intensity of inflammation by activating interleukin (IL)-1β, IL-18 and cell death by pyroptosis. How the NLRP3 inflammasome is negatively regulated is poorly understood. Here we show that NLRP3 inflammasome activation is suppressed by sumoylation. NLRP3 is sumoylated by the SUMO E3-ligase MAPL, and stimulation-dependent NLRP3 desumoylation by the SUMO-specific proteases SENP6 and SENP7 promotes NLRP3 activation. Defective NLRP3 sumoylation, either by NLRP3 mutation of SUMO acceptor lysines or depletion of MAPL, results in enhanced caspase-1 activation and IL-1β release. Conversely, depletion of SENP7 suppresses NLRP3-dependent ASC oligomerisation, caspase-1 activation and IL-1β release. These data indicate that sumoylation of NLRP3 restrains inflammasome activation, and identify SUMO proteases as potential drug targets for the treatment of inflammatory diseases.

Details

Title
SUMO-mediated regulation of NLRP3 modulates inflammasome activity
Author
Barry, Rachael 1   VIAFID ORCID Logo  ; Sidonie Wicky John 2 ; Liccardi, Gianmaria 2 ; Tenev, Tencho 2 ; Jaco, Isabel 2 ; Chih-Hong, Chen 3 ; Choi, Justin 3 ; Kasperkiewicz, Paulina 4 ; Fernandes-Alnemri, Teresa 5 ; Alnemri, Emad 5 ; Drag, Marcin 4 ; Chen, Yuan 3 ; Meier, Pascal 2 

1  The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Mary-Jean Mitchell Green Building, Chester Beatty Laboratories, London, UK; MRC Centre for Molecular Bacteriology and Infection, Department of Life Sciences, Imperial College London, London, UK 
2  The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Mary-Jean Mitchell Green Building, Chester Beatty Laboratories, London, UK 
3  Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, California, USA 
4  Division of Bioorganic Chemistry, Department of Chemistry, Wroclaw University of Technology, Wroclaw, Poland 
5  Department of Biochemistry and Molecular Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA 
Pages
1-14
Publication year
2018
Publication date
Aug 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-05321-2
ProQuest document ID
2081522793
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.