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Cathepsin B-Mediated Activation of the Proinflammatory Caspase-11

https://doi.org/10.1006/bbrc.1998.9425Get rights and content

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 caspasesin vitroled 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.

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    Abbreviations used: Ac-YVAD.cmk, acetyl-Tyr-Val-Ala-Asp(Ome)-cmk; AFC, 7-amino-4-trimethyl coumarin; AMC, 7-amino-4-methyl coumarin; Apaf, apoptotic protease activating factor; CASP, caspase; CFS, cell free system; cmk, chloromethyl ketone; EST, expressed sequence tag; fmk, fluoromethyl ketone; HM, heavy membrane fraction; IL-1;gb:interleukin-1;gb; LPS, lipopolysacharide; PAGE, polyacrylamide gel electrophoresis; PCR, polymerase chain reaction; PMSF, phenylmethylsulphonyl fluoride; TNF, tumor necrosis factor; TNF-R, TNF receptor; TPCK, N-;ga-tosyl-L-phenylalanine chloromethyl ketone; z-AAD.cmk, benzyloxycarbonyl-ala-Ala-Asp(Ome)-cmk; z-ARR.AFC, benzyloxycarbonyl-Ala-Arg-Arg-AFC; Ac-DEVD.AMC, acetyl-Asp-Glu-Val-Asp-AMC; z-FA.fmk, benzyloxycarbonyl-Phe-Ala-fmk; z-VAD.fmk, benzyloxycarbonyl-Val-Ala-Asp(OMe)-fmk

    1

    Present address: Devgen N.V., Technologiepark 9 Blok DF1.60.14; B-9052 Zwijnaarde, Belgium.

    2

    To whom correspondence should be addressed. Fax: 32-9-2645348. E-mail:[email protected].

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