Deubiquitinases Regulate the Activity of Caspase-1 and Interleukin-1β Secretion via Assembly of the Inflammasome

Abstract

Background: The inflammasome is a multimolecular complex that regulates the processing of the pro-inflammatory cytokine interleukin-1β.Results: Inhibitors of deubiquitinase (DUB) enzymes inhibited the release of interleukin-1β.Conclusion: DUBs regulate assembly of the inflammasome.Significance: DUBs may represent new anti-inflammatory drug targets for the treatment of inflammatory disease.

Nedd8 Regulates Inflammasome-Dependent Caspase-1 Activation

“…In that regard, deubiquitinase enzymes (DUBs) have been demonstrated to regulate inflammasome activity (73)(74)(75). Previous studies have shown that DUB inhibitors reduces ASC oligomerization and IL-1␤ release (74,75). Ubiquitinated NLRP3 was detected when cells were treated with DUB inhibitors, and ASC ubiquitination was observed during AIM2-mediated inflammasome activation (74)(75)(76).…”

“…Previous studies have shown that DUB inhibitors reduces ASC oligomerization and IL-1␤ release (74,75). Ubiquitinated NLRP3 was detected when cells were treated with DUB inhibitors, and ASC ubiquitination was observed during AIM2-mediated inflammasome activation (74)(75)(76). In that scenario, it is possible that silencing of Nedd8 or inhibiting neddylation prevents ubiquitination/deubiquitination, which will lead to diminished caspase-1 activation and IL-1␤ maturation.…”

“…So far, no studies have directly shown that inhibiting ubiquitination adversely affects inflammasome activation and IL-1␤ release, although a study demonstrated that the cIAP (cIAP 1 and 2) E3 ubiquitin ligase is involved in caspase-1 ubiquitination and that lack of cIAP results in loss of caspase-1 activation (77). Moreover, proteasomal inhibitors did not have an effect on inflammasome activation and IL-1␤ release from both human and murine macrophages (75). In that regard, a recent study detected caspase-1 ubiquitination following inflammasome activation (78).…”

“…Cullins are well-characterized neddylated proteins (64,65), and neddylated cullins (cullins 1, 2, and 3 are parts of SCF, SOCS, and BTB E3 ubiquitin ligase, respectively) are involved in ubiquitination of target proteins. In that regard, deubiquitinase enzymes (DUBs) have been demonstrated to regulate inflammasome activity (73)(74)(75). Previous studies have shown that DUB inhibitors reduces ASC oligomerization and IL-1␤ release (74,75).…”

AIM2 and NLRC4 inflammasomes contribute with ASC to acute brain injury independently of NLRP3

“…This raises the possibility of specific host protein DAMPs that are homologous with bacterial NAIP ligands, or that certain DAMPs or tissue/cellular stresses activate posttranslational mechanisms, causing activation of NLRC4. Recent work from our group and others has identified ubiquitin posttranslational modification of NLRP3 inflammasome components as a key integrator of diverse DAMP signals (35)(36)(37)(38). Interestingly, ubiquitination has also been suggested to regulate the activation of NLRC4 in a model of caspase-8-dependent cell death (39).…”