Cathepsin B-Mediated Activation of the Proinflammatory Caspase-11

Schotte, Peter; Criekinge, Wim Van; Craen, Marc Van de; Loo, Geert; Desmedt, Marjory; Grooten, Johan; Cornelissen, Maria; Ridder, Leo De; Vandekerckhove, Joël; Fiers, Walter; Vandenabeele, Peter; Beyaert, Rudi

doi:10.1006/bbrc.1998.9425

Cited by 140 publications

(108 citation statements)

References 33 publications

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“…Thus, it has been suggested that CB would directly activate caspase-11 (Schotte et al, 1998) and/or trigger apoptotic chromatin condensation and nuclear DNA loss ( Vancompernolle et al, 1998). However, the presence of CB in the nucleus is not sufficient to induce apoptosis, as shown by the fact that Bax À/À Bak À/À cells can release cathepsin from lysosomes, yet manifest a normal chromatin structure and fail to translocate cytochrome c (Figure 7).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial membrane permeabilization is a critical step of lysosome-initiated apoptosis induced by hydroxychloroquine

et al. 2003

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Hydroxychloroquine (HCQ) is a lysosomotropic amine with cytotoxic properties. Here, we show that HCQ induces signs of lysosomal membrane permeabilization (LMP), such as the decrease in the lysosomal pH gradient and the release of cathepsin B from the lysosomal lumen, followed by signs of apoptosis including caspase activation, phosphatidylserine exposure, and chromatin condensation with DNA loss. HCQ also induces mitochondrial membrane permeabilization (MMP), as indicated by the insertion of Bax into mitochondrial membranes, the conformational activation of Bax within mitochondria, the release of cytochrome c from mitochondria, and the loss of the mitochondrial transmembrane potential. To determine the molecular order among these events, we introduced inhibitors of LMP (bafilomycin A 1 ), MMP (Bcl-X L , wild-type Bcl-2, mitochondrion-targeted Bcl-2, or viral mitochondrial inhibitor of apoptosis from cytomegalovirus), and caspases (Z-VAD.fmk) into the system. Our data indicate that caspase-independent MMP is rate-limiting for LMP-mediated caspase activation. Mouse embryonic fibroblasts lacking the expression of both Bax and Bak are resistant against hydroxychloroquine-induced apoptosis. Such Bax À/À Bak À/À cells manifest normal LMP, yet fail to undergo MMP and subsequent cell death. The data reported herein indicate that LMP does not suffice to trigger caspase activation and that Bax/Bak-dependent MMP is a critical step of LMP-induced cell death.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial membrane permeabilization is a critical step of lysosome-initiated apoptosis induced by hydroxychloroquine

et al. 2003

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“…24 Alternatively, cathepsins could cleave and activate caspases or their downstream death effector substrates, 25 thereby causing apoptosis. In support of the former mechanism, it has been shown that cathepsin B can activate the inflammatory caspases 1 and 11, 17,26 and that cathepsin L may activate caspase-3. 20 The final possible mode of cathepsin action places cathepsins far upstream in the apoptotic cascade, cleaving the proapoptotic Bcl-2 family member Bid to initiate mitochondrial release of cytochrome c. This last hypothesis received in vitro confirmation when it was shown that lysosomal extracts containing cathepsins were able to cleave purified Bid in a physiologically relevant manner that supported apoptosis.…”

Section: Introductionmentioning

confidence: 89%

Apoptosis caused by cathepsins does not require Bid signaling in an in vivo model of progressive myoclonus epilepsy (EPM1)

Vilaythong

Yin

et al. 2003

Cell Death Differ

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Apoptosis can be mediated by mechanisms other than the traditional caspase-mediated cleavage cascade. There is growing recognition that alternative proteolytic enzymes such as the lysosomal cathepsin proteases can initiate or propagate proapoptotic signals, but it is currently unclear how cathepsins achieve these actions. Recent in vitro evidence suggests that cathepsins cleave the proapoptotic Bcl-2 family member Bid, thereby activating it and allowing it to induce the mitochondrial release of cytochrome c and subsequent apoptosis. We have tested this hypothesis in vivo by breeding mice that lack cathepsin inhibition (cystatin B-deficient mice) to Bid-deficient mice, to determine whether the apoptosis caused by cathepsins is dependent on Bid signaling. We found that cathepsins are still able to promote apoptosis even in the absence of Bid, indicating that these proteases mediate apoptosis via a different pathway, or that some other molecule can functionally substitute for Bid in this system.

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“…Livers of wild-type and Bcl-2-transgenic mice were homogenized in homogenization buffer (5 mM KH 2 PO 4 pH 7.4, 0.3 M sucrose, 1 mM EGTA, 5 mM 3-(N-morpholino)propanesulfonic acid). Mitochondria were purified as described previously 39,72 and resuspended in cell-free system buffer (10 mM HEPES-NaOH pH 7.4, 220 mM mannitol, 68 mM sucrose, 2 mM NaCl, 2.5 mM KH 2 PO 4 , 0.5 mM EGTA, 2 mM MgCl 2 , 5 mM pyruvate, 0.1 mM PMSF, and 1 mM dithiothreitol), kept on ice and used within 1 h of preparation.…”

Section: Methodsmentioning

confidence: 99%

A matrix-assisted laser desorption ionization post-source decay (MALDI-PSD) analysis of proteins released from isolated liver mitochondria treated with recombinant truncated Bid

et al. 2002

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A crucial event in the process of apoptosis is caspasedependent generation of truncated Bid (tBid), inducing release of cytochrome c. In an in vitro reconstitution system we combined purified recombinant tBid with isolated liver mitochondria and identified the released proteins using a proteomic matrix-assisted laser desorption ionization postsource decay (MALDI-PSD) approach. In order to meet physiological conditions, the concentration of tBid was chosen such that it was unable to induce cytochrome c release in mitochondriaderivedfrom liver-specificBcl-2-transgenicmice. Several mitochondrial proteins were identified to be released in a tBid-dependent way, among which cytochrome c, DIABLO/ Smac, adenylate kinase 2, acyl-CoA-binding protein, endonuclease G, polypyrimidine tract-binding protein, a type-I RNA helicase, a WD-40 repeat-containing protein and the serine protease Omi. Western blotting confirmed the absence of adenylate kinase 3, a matrix mitochondrial protein. These results demonstrate that a physiologically relevant concentration of tBid is sufficient to induce release of particular intermembrane mitochondrial proteins belonging to a broad molecular-mass range.

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Cathepsin B-Mediated Activation of the Proinflammatory Caspase-11

Cited by 140 publications

References 33 publications

Mitochondrial membrane permeabilization is a critical step of lysosome-initiated apoptosis induced by hydroxychloroquine

Mitochondrial membrane permeabilization is a critical step of lysosome-initiated apoptosis induced by hydroxychloroquine

Apoptosis caused by cathepsins does not require Bid signaling in an in vivo model of progressive myoclonus epilepsy (EPM1)

A matrix-assisted laser desorption ionization post-source decay (MALDI-PSD) analysis of proteins released from isolated liver mitochondria treated with recombinant truncated Bid

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