The caspase-1 digestome identifies the glycolysis pathway as a target during infection and septic shock.
Caspase-1 is an essential effector of inflammation, pyroptosis, and septic shock. Few caspase-1 substrates have been identified to date, and these substrates do not account for its wide range of actions. To understand the function of caspase-1, we initiated the systematic identification of its cellular substrates. Using the diagonal gel proteomic approach, we identified 41 proteins that are directly cleaved by caspase-1. Among these were chaperones, cytoskeletal and translation machinery proteins, and proteins involved in immunity. A series of unexpected proteins along the glycolysis pathway were also identified, including aldolase, triose-phosphate isomerase, glyceraldehyde-3-phosphate dehydrogenase, alpha-enolase, and pyruvate kinase. With the exception of the latter, the identified glycolysis enzymes were specifically cleaved in vitro by recombinant caspase-1, but not caspase-3. The enzymatic activity of wild-type glyceraldehyde-3-phosphate dehydrogenase, but not a non-cleavable mutant, was dampened by caspase-1 processing. In vivo, stimuli that fully activated caspase-1, including Salmonella typhimurium infection and septic shock, caused a pronounced processing of these proteins in the macrophage and diaphragm muscle, respectively. Notably, these stimuli inhibited glycolysis in wild-type cells compared with caspase-1-deficient cells. The systematic characterization of caspase-1 substrates identifies the glycolysis pathway as a caspase-1 target and provides new insights into its function during pyroptosis and septic shock.
Shao
Wei
W
Department of Biochemistry, Division of Critical Care, Centre for the Study of Host Resistance, McGill University, Montreal, Quebec, Canada.
Yeretssian
Garabet
G
Doiron
Karine
K
Hussain
Sabah N
SN
Saleh
Maya
M
D000818:Animals; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003964:Diaphragm / Q000201:enzymology / Q000473:pathology; D006019:Glycolysis; D006801:Humans; D017737:Macrophages, Peritoneal / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D020543:Proteome / Q000235:genetics / Q000378:metabolism; D012480:Salmonella Infections / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D012486:Salmonella typhimurium; D012772:Shock, Septic / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D013379:Substrate Specificity / Q000235:genetics
D020543:Proteome; D020170:Caspase 1