Cardiolipin inhibits the non-canonical inflammasome by preventing LPS binding to caspase-4/11
Malvina Pizzuto, Mercedes Monteleone, Sabrina Sofia Burgener, Jakub Began, Melan Kurera, J. K. S. Chia, Emmanuelle Frampton, Joanna Crawford, Monalisa Oliveira, Kirsten M. Kenney, J. Coombs, Masahiro Yamamoto, Si Ming Man, Petr Brož, Pablo Pelegrı́n, Kate Schroder
Abstract
Caspase-4 and caspase-11 (CASP4/11) sense bacterial lipopolysaccharide (LPS). Currently available inhibitors of CASP4/11 also block the activity of caspase-1 (CASP1), which restricts their usefulness in the study of CASP4/11 functions, as well as their clinical potential for the treatment of LPS-linked diseases through CASP4/11 inhibition. Here, we identify mitochondrial cardiolipin as a selective inhibitor of CASP4/11-dependent cell death and inflammatory cytokine secretion, without affecting CASP1 function. Cardiolipin targets the CARD domain of CASP4/11, impeding its interaction with LPS to restrain CASP4/11 activation, thereby suppressing LPS-induced systemic inflammation in vivo. By identifying cardiolipin as a selective inhibitor of CASP4/11, we provide an urgently needed tool for studying caspase-4/11 and noncanonical inflammasome functions in inflammatory pathways and LPS-induced pathogenesis.