Universität zu Köln

Fritsch, Melanie, Gunther, Saskia D., Schwarzer, Robin, Albert, Marie-Christine, Schorn, Fabian, Werthenbach, J. Paul, Schiffmann, Lars M., Stair, Neil, Stocks, Hannah ORCID: 0000-0002-4129-5138, Seeger, Jens M., Lamkanfi, Mohamed, Kroenke, Martin, Pasparakis, Manolis ORCID: 0000-0002-9870-0966 and Kashkar, Hamid (2019). Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis. Nature, 575 (7784). S. 683 - 700. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-4687

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Abstract

Caspase-8 is the initiator caspase of extrinsic apoptosis(1,2) and inhibits necroptosis mediated by RIPK3 and MLKL. Accordingly, caspase-8 deficiency in mice causes embryonic lethality(3), which can be rescued by deletion of either Ripk3 or Mlkl(4-6). Here we show that the expression of enzymatically inactive CASP8(C362S) causes embryonic lethality in mice by inducing necroptosis and pyroptosis. Similar to Casp8(-/-) mice(3,7), Casp8(C362S/C362S) mouse embryos died after endothelial cell necroptosis leading to cardiovascular defects. MLKL deficiency rescued the cardiovascular phenotype but unexpectedly caused perinatal lethality in Casp8(C362S/C362S) mice, indicating that CASP8(C362S) causes necroptosis-independent death at later stages of embryonic development. Specific loss of the catalytic activity of caspase-8 in intestinal epithelial cells induced intestinal inflammation similar to intestinal epithelial cell-specific Casp8 knockout mice(8). Inhibition of necroptosis by additional deletion of Mlkl severely aggravated intestinal inflammation and caused premature lethality in Mlkl knockout mice with specific loss of caspase-8 catalytic activity in intestinal epithelial cells. Expression of CASP8(C362S) triggered the formation of ASC specks, activation of caspase-1 and secretion of IL-1 beta. Both embryonic lethality and premature death were completely rescued in Casp8(C362S/C362S)Mlkl(-/-)Asc(-/-) or Casp8(C362S/C362S)Mlkl(-/-)Casp1(-/-) mice, indicating that the activation of the inflammasome promotes CASP8(C362S)-mediated tissue pathology when necroptosis is blocked. Therefore, caspase-8 represents the molecular switch that controls apoptosis, necroptosis and pyroptosis, and prevents tissue damage during embryonic development and adulthood.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Fritsch, Melanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Gunther, Saskia D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schwarzer, Robin UNSPECIFIED UNSPECIFIED UNSPECIFIED Albert, Marie-Christine UNSPECIFIED UNSPECIFIED UNSPECIFIED Schorn, Fabian UNSPECIFIED UNSPECIFIED UNSPECIFIED Werthenbach, J. Paul UNSPECIFIED UNSPECIFIED UNSPECIFIED Schiffmann, Lars M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Stair, Neil UNSPECIFIED UNSPECIFIED UNSPECIFIED Stocks, Hannah UNSPECIFIED orcid.org/0000-0002-4129-5138 UNSPECIFIED Seeger, Jens M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lamkanfi, Mohamed UNSPECIFIED UNSPECIFIED UNSPECIFIED Kroenke, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED Kashkar, Hamid UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-126894
DOI:	10.1038/s41586-019-1770-6
Journal or Publication Title:	Nature
Volume:	575
Number:	7784
Page Range:	S. 683 - 700
Date:	2019
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1476-4687
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language INFLAMMASOME; REQUIREMENT; ACTIVATION; EXPRESSION; PROMOTES; PROTEASE; MOUSE; FADD Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/12689