Branched-chain amino acid sensing anabolically licenses NLRP3 inflammasome assembly and IL-1 cytokine release 2168

Abstract Description The NLRP3 inflammasome is a multiprotein complex that triggers pyroptosis during infection and cell injury. Its assembly is mediated by the adaptor protein ASC, whose aggregation amplifies proximity-induced caspase-1 autoproteolysis. Although the molecular events that promote inflammasome triggering are extensively documented, their regulation by metabolite sensing pathways remains poorly understood. Here, using a novel metabolic screen entailing macrophage starvation of individual and defined groups of amino acids, we identify sensing of the essential branched-chain amino acids (BCAAs) leucine, isoleucine, and valine as a critical signal for anabolically licensing NLRP3 inflammasome activation. Provision of the BCAAs during TLR4-driven inflammasome priming is required for subsequent NLRP3-triggered ASC speck assembly, caspase-1 cleavage, membrane permeability, and IL-1 release. Mechanistically, polysome profiling revealed that TLR4 activation promotes IL-1 and ASC translational bursting from polyribosomes, an effect that is thwarted in BCAA-starved macrophages, which are otherwise only modestly impaired in their priming of NLRP3. In vivo, dietary restriction of the BCAAs protected mice from mortality in an inflammasome-driven model of endotoxic shock. We therefore propose that BCAA sensing during TLR4 activation is translationally required to both prime IL-1 and locally concentrate ASC expression for enabling oligomerization of the inflammasome speck upon NLRP3 activation. Funding Sources Supported by American Heart Association Postdoctoral Fellowship and NIH/NIAID R01AI118861 Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)