Lin, Juan, Kumari, Snehlata, Kim, Chun ORCID: 0000-0001-9497-708X, Van, Trieu-My, Wachsmuth, Laurens, Polykratis, Apostolos ORCID: 0000-0001-6720-3302 and Pasparakis, Manolis ORCID: 0000-0002-9870-0966 (2016). RIPK1 counteracts ZBP1-mediated necroptosis to inhibit inflammation. Nature, 540 (7631). S. 124 - 137. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-4687

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Abstract

Receptor-interacting protein kinase 1 (RIPK1) regulates cell death and inflammation through kinase-dependent and -independent functions(1-7). RIPK1 kinase activity induces caspase-8-dependent apoptosis and RIPK3 and mixed lineage kinase like (MLKL)-dependent necroptosis(8-13). In addition, RIPK1 inhibits apoptosis and necroptosis through kinase-independent functions, which are important for late embryonic development and the prevention of inflammation in epithelial barriers(14-18). The mechanism by which RIPK1 counteracts RIPK3-MLKL-mediated necroptosis has remained unknown. Here we show that RIPK1 prevents skin inflammation by inhibiting activation of RIPK3-MLKL-dependent necroptosis mediated by Z-DNA binding protein 1 (ZBP1, also known as DAI or DLM1). ZBP1 deficiency inhibited keratinocyte necroptosis and skin inflammation in mice with epidermis-specific RIPK1 knockout. Moreover, mutation of the conserved RIP homotypic interaction motif (RHIM) of endogenous mouse RIPK1 (RIPK1(mRHIM)) caused perinatal lethality that was prevented by RIPK3, MLKL or ZBP1 deficiency. Furthermore, mice expressing only RIPK1(mRHIM) in keratinocytes developed skin inflammation that was abrogated by MLKL or ZBP1 deficiency. Mechanistically, ZBP1 interacted strongly with phosphorylated RIPK3 in cells expressing RIPK1(mRHIM), suggesting that the RIPK1 RHIM prevents ZBP1 from binding and activating RIPK3. Collectively, these results show that RIPK1 prevents perinatal death as well as skin inflammation in adult mice by inhibiting ZBP1-induced necroptosis. Furthermore, these findings identify ZBP1 as a critical mediator of inflammation beyond its previously known role in antiviral defence and suggest that ZBP1 might be implicated in the pathogenesis of necroptosis-associated inflammatory diseases.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Lin, JuanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kumari, SnehlataUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kim, ChunUNSPECIFIEDorcid.org/0000-0001-9497-708XUNSPECIFIED
Van, Trieu-MyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wachsmuth, LaurensUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Polykratis, ApostolosUNSPECIFIEDorcid.org/0000-0001-6720-3302UNSPECIFIED
Pasparakis, ManolisUNSPECIFIEDorcid.org/0000-0002-9870-0966UNSPECIFIED
URN: urn:nbn:de:hbz:38-254985
DOI: 10.1038/nature20558
Journal or Publication Title: Nature
Volume: 540
Number: 7631
Page Range: S. 124 - 137
Date: 2016
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 1476-4687
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CELL-DEATH; PROGRAMMED NECROSIS; INNATE; HOMEOSTASIS; ACTIVATION; CASPASE-8; MICEMultiple languages
Multidisciplinary SciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/25498

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