Cathepsin D primes caspase-8 activation by multiple intra-chain proteolysis

Conus, Sébastien; Pop, Cristina; Snipas, Scott J; Salvesen, Guy S; Simon, Hans-Uwe (2012). Cathepsin D primes caspase-8 activation by multiple intra-chain proteolysis. Journal of biological chemistry, 287(25), pp. 21142-51. Bethesda, Md.: American Society for Biochemistry and Molecular Biology 10.1074/jbc.M111.306399

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During the resolution of inflammatory responses, neutrophils rapidly undergo apoptosis. A direct and fast activation of caspase-8 by cathepsin D was shown to be crucial in the initial steps of neutrophil apoptosis. Nevertheless, the activation mechanism of caspase-8 remains unclear. Here, by using site-specific mutants of caspase-8, we show that both cathepsin D-mediated proteolysis and homodimerization of caspase-8 are necessary to generate an active caspase-8. At acidic pH, cathepsin D specifically cleaved caspase-8 but not the initiator caspase-9 or -10 and significantly increased caspase-8 activity in dimerizing conditions. These events were completely abolished by pepstatin A, a pharmacological inhibitor of cathepsin D. The cathepsin D intra-chain proteolysis greatly stabilized the active site of caspase-8. Moreover, the main caspase-8 fragment generated by cathepsin D cleavage could be affinity-labeled with the active site probe biotin-VAD-fluoromethyl ketone, suggesting that this fragment is enzymatically active. Importantly, in an in vitro cell-free assay, the addition of recombinant human caspase-8 protein, pre-cleaved by cathepsin D, was followed by caspase-3 activation. Our data therefore indicate that cathepsin D is able to initiate the caspase cascade by direct activation of caspase-8. As cathepsin D is ubiquitously expressed, this may represent a general mechanism to induce apoptosis in a variety of immune and nonimmune cells.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology
UniBE Contributor:	Simon, Hans-Uwe
ISSN:	0021-9258
Publisher:	American Society for Biochemistry and Molecular Biology
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 14:35
Last Modified:	05 Dec 2022 14:11
Publisher DOI:	10.1074/jbc.M111.306399
PubMed ID:	22528489
Web of Science ID:	000306416800035
URI:	https://boris.unibe.ch/id/eprint/14107 (FactScience: 220916)