SUMO-mediated regulation of NLRP3 modulates inflammasome activity

Nat Commun. 2018 Aug 1;9(1):3001. doi: 10.1038/s41467-018-05321-2.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Endopeptidases / metabolism
  • HEK293 Cells
  • Humans
  • Inflammasomes / metabolism*
  • Interleukin-1beta / metabolism
  • Lysine / genetics
  • Mice
  • Mutation / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / chemistry
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Protein Binding
  • Small Ubiquitin-Related Modifier Proteins / metabolism*
  • Sumoylation
  • Ubiquitin-Protein Ligases / metabolism


  • Inflammasomes
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Small Ubiquitin-Related Modifier Proteins
  • MUL1 protein, human
  • Ubiquitin-Protein Ligases
  • Endopeptidases
  • SENP7 protein, mouse
  • Lysine