Superoxide dismutase 1 regulates caspase-1 and endotoxic shock.
Caspase-1 serves an essential function in the initiation of inflammation by proteolytically maturing the cytokines interleukin 1 beta and interleukin 18. Several Nod-like receptors activate caspase-1 in response to microbial and 'danger' signals by assembling cytosolic protein complexes called 'inflammasomes'. We show here that superoxide dismutase 1 (SOD1) regulates caspase-1 activation. In SOD1-deficient macrophages, higher superoxide production decreased the cellular redox potential and specifically inhibited caspase-1 by reversible oxidation and glutathionylation of the redox-sensitive cysteine residues Cys397 and Cys362. Conversely, hypoxic conditions abrogated caspase-1 inhibition. In vivo, SOD1-deficient mice produced less caspase-1-dependent cytokines and were less susceptible to lipopolysaccharide-induced septic shock. Our findings identify a physiological post-translational mechanism in the control of caspase-1-mediated inflammatory processes.
Meissner
Felix
F
Department of Cellular Microbiology, Max Planck Institute for Infection Biology, 10117 Berlin, Germany.
Molawi
Kaaweh
K
Zychlinsky
Arturo
A
D000818:Animals; D020170:Caspase 1 / Q000378:metabolism*; D004731:Endotoxins / Q000378:metabolism*; D004789:Enzyme Activation; D007249:Inflammation / Q000276:immunology*; D008070:Lipopolysaccharides / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D012772:Shock, Septic; D013482:Superoxide Dismutase / Q000172:deficiency / Q000276:immunology / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
D004731:Endotoxins; D008070:Lipopolysaccharides; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D020170:Caspase 1