SUMO-mediated regulation of NLRP3 modulates inflammasome activity.
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Date
2018-08-01ICR Author
Author
Barry, R
John, SW
Liccardi, G
Tenev, T
Jaco, I
Chen, C-H
Choi, J
Kasperkiewicz, P
Fernandes-Alnemri, T
Alnemri, E
Drag, M
Chen, Y
Meier, P
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Animals
Humans
Mice
Endopeptidases
Ubiquitin-Protein Ligases
Lysine
Small Ubiquitin-Related Modifier Proteins
Amino Acid Sequence
Protein Binding
Mutation
Interleukin-1beta
HEK293 Cells
Sumoylation
Inflammasomes
NLR Family, Pyrin Domain-Containing 3 Protein
Research team
Cell Death and Immunity
Language
eng
Date accepted
2018-07-01
License start date
2018-08
Citation
Nature communications, 2018, 9 (1), pp. 3001 - ?
Publisher
NATURE PUBLISHING GROUP