Editors' ChoiceImmunology

Inflammasome SUMOylation

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Science Signaling  14 Aug 2018:
Vol. 11, Issue 543, eaau2212
DOI: 10.1126/scisignal.aau2212

NLRP3 inflammasome activity is inhibited by SUMOylation.

Inflammasomes are innate immune signaling complexes that are activated by cellular infection or stress. Composed of distinct intracellular sensors bound to the adaptor protein ASC, inflammasomes stimulate the caspase-1–mediated maturation of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18. Emerging evidence suggests that posttranslational modifications, such as phosphorylation and ubiquitylation, may regulate inflammasome activity. Barry et al. found that covalent reversible attachment of SUMO proteins (SUMOylation) to the inflammasome component NLRP3 also inhibited its activity. In unstimulated mouse macrophages and 293T cells, NLRP3 was basally conjugated to SUMO-2/3. Mutation of the surface-exposed SUMO-acceptor lysine residues enhanced NLRP3-mediated caspase-1 activation in a 293T cell inflammasome reconstitution system. SUMOylation of NLRP3 was mediated by MAPL, a mitochondrially localized SUMO E3 ligase. Knockdown of this enzyme increased caspase-1 activity and IL-1β production in bone marrow–derived macrophages treated with the microbial toxin nigericin, which activates NLRP3 inflammasomes. Conversely, knockdown of the SUMO deconjugating enzymes Senp6 and Senp7 reduced ASC oligomerization, caspase-1 activation, and IL-1β release. Treatment of wild-type macrophages with nigericin reduced the abundance of SUMOylated NLRP3. These data suggest that SUMOylation of NLRP3 inhibits inflammasome activity and that this posttranslational modification may itself be limited by microbial recognition.

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