Universität zu Köln

Jaco, Isabel, Annibaldi, Alessandro ORCID: 0000-0002-0346-4340, Lalaoui, Najoua ORCID: 0000-0002-0165-3324, Wilson, Rebecca, Tenev, Tencho, Laurien, Lucie, Kim, Chun ORCID: 0000-0001-9497-708X, Jamal, Kunzah, John, Sidonie Wicky, Liccardi, Gianmaria, Chau, Diep, Murphy, James M., Brumatti, Gabriela, Feltham, Rebecca, Pasparakis, Manolis ORCID: 0000-0002-9870-0966, Silke, John ORCID: 0000-0002-7611-5774 and Meier, Pascal ORCID: 0000-0003-2760-6523 (2017). MK2 Phosphorylates RIPK1 to Prevent TNF-Induced Cell Death. Mol. Cell, 66 (5). S. 698 - 716. CAMBRIDGE: CELL PRESS. ISSN 1097-4164

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Abstract

TNF is an inflammatory cytokine that upon binding to its receptor, TNFR1, can drive cytokine production, cell survival, or cell death. TNFR1 stimulation causes activation of NF-kappa B, p38 alpha, and its downstream effector kinase MK2, thereby promoting transcription, mRNA stabilization, and translation of target genes. Here we show that TNF-induced activation of MK2 results in global RIPK1 phosphorylation. MK2 directly phosphorylates RIPK1 at residue S321, which inhibits its ability to bind FADD/caspase-8 and induce RIPK1-kinase-dependent apoptosis and necroptosis. Consistently, a phospho-mimetic S321D RIPK1 mutation limits TNF-induced death. Mechanistically, we find that phosphorylation of S321 inhibits RIPK1 kinase activation. We further show that cytosolic RIPK1 contributes to complex-II-mediated cell death, independent of its recruitment to complex-I, suggesting that complex-II originates from both RIPK1 in complex-I and cytosolic RIPK1. Thus, MK2-mediated phosphorylation of RIPK1 serves as a checkpoint within the TNF signaling pathway that integrates cell survival and cytokine production.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Jaco, Isabel UNSPECIFIED UNSPECIFIED UNSPECIFIED Annibaldi, Alessandro UNSPECIFIED orcid.org/0000-0002-0346-4340 UNSPECIFIED Lalaoui, Najoua UNSPECIFIED orcid.org/0000-0002-0165-3324 UNSPECIFIED Wilson, Rebecca UNSPECIFIED UNSPECIFIED UNSPECIFIED Tenev, Tencho UNSPECIFIED UNSPECIFIED UNSPECIFIED Laurien, Lucie UNSPECIFIED UNSPECIFIED UNSPECIFIED Kim, Chun UNSPECIFIED orcid.org/0000-0001-9497-708X UNSPECIFIED Jamal, Kunzah UNSPECIFIED UNSPECIFIED UNSPECIFIED John, Sidonie Wicky UNSPECIFIED UNSPECIFIED UNSPECIFIED Liccardi, Gianmaria UNSPECIFIED UNSPECIFIED UNSPECIFIED Chau, Diep UNSPECIFIED UNSPECIFIED UNSPECIFIED Murphy, James M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Brumatti, Gabriela UNSPECIFIED UNSPECIFIED UNSPECIFIED Feltham, Rebecca UNSPECIFIED UNSPECIFIED UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED Silke, John UNSPECIFIED orcid.org/0000-0002-7611-5774 UNSPECIFIED Meier, Pascal UNSPECIFIED orcid.org/0000-0003-2760-6523 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-230114
DOI:	10.1016/j.molcel.2017.05.003
Journal or Publication Title:	Mol. Cell
Volume:	66
Number:	5
Page Range:	S. 698 - 716
Date:	2017
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	1097-4164
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; SPATA2 LINKS CYLD; SIGNALING COMPLEX; KINASE-ACTIVITY; UBIQUITIN; INFLAMMATION; ACTIVATION; NECROPTOSIS; APOPTOSIS; TARGET Multiple languages Biochemistry & Molecular Biology; Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/23011