Universität zu Köln

Priem, Dario ORCID: 0000-0002-2527-1101, Devos, Michael ORCID: 0000-0001-9522-6026, Druwe, Sarah, Martens, Arne, Slowicka, Karolina, Ting, Adrian T., Pasparakis, Manolis ORCID: 0000-0002-9870-0966, Declerq, Wim, Vandenabeele, Peter, van Loo, Geert and Bertrand, Mathieu J. M. (2019). A20 protects cells from TNF-induced apoptosis through linear ubiquitin-dependent and -independent mechanisms. Cell Death Dis., 10. LONDON: NATURE PUBLISHING GROUP. ISSN 2041-4889

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Abstract

The cytokine TNF promotes inflammation either directly by activating the MAPK and NF-kappa B signaling pathways, or indirectly by triggering cell death. A20 is a potent anti-inflammatory molecule, and mutations in the gene encoding A20 are associated with a wide panel of inflammatory pathologies, both in human and in the mouse. Binding of TNF to TNFR1 triggers the NF-kappa B-dependent expression of A20 as part of a negative feedback mechanism preventing sustained NF-kappa B activation. Apart from acting as an NF-kappa B inhibitor, A20 is also well-known for its ability to counteract the cytotoxic potential of TNF. However, the mechanism by which A20 mediates this function and the exact cell death modality that it represses have remained incompletely understood. In the present study, we provide in vitro and in vivo evidences that deletion of A20 induces RIPK1 kinase-dependent and -independent apoptosis upon single TNF stimulation. We show that constitutively expressed A20 is recruited to TNFR1 signaling complex (Complex I) via its seventh zinc finger (ZF7) domain, in a cIAP1/2-dependent manner, within minutes after TNF sensing. We demonstrate that Complex I-recruited A20 protects cells from apoptosis by stabilizing the linear (M1) ubiquitin network associated to Complex I, a process independent of its E3 ubiquitin ligase and deubiquitylase (DUB) activities and which is counteracted by the DUB CYLD, both in vitro and in vivo. In absence of linear ubiquitylation, A20 is still recruited to Complex I via its ZF4 and ZF7 domains, but this time protects the cells from death by deploying its DUB activity. Together, our results therefore demonstrate two distinct molecular mechanisms by which constitutively expressed A20 protect cells from TNF-induced apoptosis.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Priem, Dario UNSPECIFIED orcid.org/0000-0002-2527-1101 UNSPECIFIED Devos, Michael UNSPECIFIED orcid.org/0000-0001-9522-6026 UNSPECIFIED Druwe, Sarah UNSPECIFIED UNSPECIFIED UNSPECIFIED Martens, Arne UNSPECIFIED UNSPECIFIED UNSPECIFIED Slowicka, Karolina UNSPECIFIED UNSPECIFIED UNSPECIFIED Ting, Adrian T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED Declerq, Wim UNSPECIFIED UNSPECIFIED UNSPECIFIED Vandenabeele, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED van Loo, Geert UNSPECIFIED UNSPECIFIED UNSPECIFIED Bertrand, Mathieu J. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-141160
DOI:	10.1038/s41419-019-1937-y
Journal or Publication Title:	Cell Death Dis.
Volume:	10
Date:	2019
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	2041-4889
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 NF-KAPPA-B; ACTIVATION; DEATH; PHOSPHORYLATION; POLYUBIQUITIN; INFLAMMATION; COMPLEX; BINDING; CHAINS; CYLD Multiple languages Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/14116