title: Cathepsin B-mediated activation of the proinflammatory caspase-11.
abstract: Members of the caspase (CASP) family of cysteine proteases can be subdivided in proapoptotic caspases and proinflammatory caspases. Whereas the apical activation pathways for the caspases that are involved in the execution of the apoptotic process are beginning to be understood, the pathways that lead to the activation of proinflammatory caspases are still largely unknown. Analysis of subcellular fractions for their ability to process and activate several caspases in vitro led to the identification of lysosomes as the source for a protease that could proteolytically activate the proinflammatory CASP-11. Although this lysosomal activity was sensitive to caspase inhibitors, affinity purification with the biotinylated broad spectrum caspase inhibitor z-VAD.fmk revealed the CASP-11 activating protease as cathepsin B. Activation of CASP-11 by cathepsin B as well as its sensitivity to several caspase inhibitors was further confirmed with purified proteases. Similar to the role of mitochondrial factors in the activation of proapoptotic caspases, our results suggest a potential role for lysosomes and cathepsin B as activators of specific proinflammatory caspases. In addition, the aspecific inhibition of cathepsin B by so-called specific caspase inhibitors implicates that results obtained with these inhibitors should be interpreted with care.
authors.affiliation: Department of Molecular Biology, Flanders Interuniversity Institute for Biotechnology and University of Gent, K. L. Ledeganckstraat 35, Gent, B-9000, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Schotte
authors.forename: W
authors.initials: W
authors.lastname: Van Criekinge
authors.forename: M
authors.initials: M
authors.lastname: Van de Craen
authors.forename: G
authors.initials: G
authors.lastname: Van Loo
authors.forename: M
authors.initials: M
authors.lastname: Desmedt
authors.forename: J
authors.initials: J
authors.lastname: Grooten
authors.forename: M
authors.initials: M
authors.lastname: Cornelissen
authors.forename: L
authors.initials: L
authors.lastname: De Ridder
authors.forename: J
authors.initials: J
authors.lastname: Vandekerckhove
authors.forename: W
authors.initials: W
authors.lastname: Fiers
authors.forename: P
authors.initials: P
authors.lastname: Vandenabeele
authors.forename: R
authors.initials: R
authors.lastname: Beyaert
mesh_terms: D000818:Animals; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases / Q000378:metabolism*; D053471:Caspases, Initiator; D002401:Cathepsin B / Q000378:metabolism*; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism; D005260:Female; D007249:Inflammation / Q000201:enzymology; D008099:Liver / Q000166:cytology / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008956:Models, Chemical; D013347:Subcellular Fractions / Q000201:enzymology
chemical_list: D004792:Enzyme Precursors; C505409:Casp3 protein, mouse; C101136:Casp4 protein, mouse; C505524:Casp7 protein, mouse; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases; D053471:Caspases, Initiator; D002401:Cathepsin B