Lalaoui, Najoua ORCID: 0000-0002-0165-3324, Boyden, Steven E., Oda, Hirotsugu, Wood, Geryl M., Stone, Deborah L., Chau, Diep, Liu, Lin, Stoffels, Monique, Kratina, Tobias, Lawlor, Kate E., Zaal, Kristien J. M., Hoffmann, Patrycja M., Etemadi, Nima, Shield-Artin, Kristy, Biben, Christine, Tsai, Wanxia Li, Blake, Mary D., Kuehn, Hye Sun, Yang, Dan, Anderton, Holly ORCID: 0000-0003-3913-9686, Silke, Natasha, Wachsmuth, Laurens, Zheng, Lixin, Moura, Natalia Sampaio, Beck, David B., Gutierrez-Cruz, Gustavo, Ombrello, Amanda K., Pinto-Patarroyo, Gineth P., Kueh, Andrew J., Herold, Marco J., Hall, Cathrine, Wang, Hongying, Chae, Jae Jin, Dmitrieva, Natalia I., McKenzie, Mark, Light, Amanda, Barham, Beverly K., Jones, Anne, Romeo, Tina M., Zhou, Qing, Aksentijevich, Ivona, Mullikin, James C., Gross, Andrew J., Shum, Anthony K., Hawkins, Edwin D., Masters, Seth L., Lenardo, Michael J., Boehm, Manfred, Rosenzweig, Sergio D., Pasparakis, Manolis ORCID: 0000-0002-9870-0966, Voss, Anne K., Gadina, Massimo, Kastner, Daniel L. and Silke, John (2020). Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease. Nature, 577 (7788). S. 103 - 123. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-4687

Full text not available from this repository.

Abstract

RIPK1 is a key regulator of innate immune signalling pathways. To ensure an optimal inflammatory response, RIPK1 is regulated post-translationally by well-characterized ubiquitylation and phosphorylation events, as well as by caspase-8-mediated cleavage1-7. The physiological relevance of this cleavage event remains unclear, although it is thought to inhibit activation of RIPK3 and necroptosis8. Here we show that the heterozygous missense mutations D324N, D324H and D324Y prevent caspase cleavage of RIPK1 in humans and result in an early-onset periodic fever syndrome and severe intermittent lymphadenopathy-a condition we term 'cleavage-resistant RIPK1-induced autoinflammatory syndrome'. To define the mechanism for this disease, we generated a cleavage-resistant Ripk1(D325A) mutant mouse strain. Whereas Ripk1(-/-) mice died postnatally from systemic inflammation, Ripk1(D325A/D325A) mice died during embryogenesis. Embryonic lethality was completely prevented by the combined loss of Casp8 and Ripk3, but not by loss of Ripk3 or Mlkl alone. Loss of RIPK1 kinase activity also prevented Ripk1(D325A/D325A) embryonic lethality, although the mice died before weaning from multi-organ inflammation in a RIPK3-dependent manner. Consistently, Ripk1(D325A/D325A) and Ripk1(D325A/+) cells were hypersensitive to RIPK3-dependent TNF-induced apoptosis and necroptosis. Heterozygous Ripk1(D325A/+) mice were viable and grossly normal, but were hyper-responsive to inflammatory stimuli in vivo. Our results demonstrate the importance of caspase-mediated RIPK1 cleavage during embryonic development and show that caspase cleavage of RIPK1 not only inhibits necroptosis but also maintains inflammatory homeostasis throughout life.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Lalaoui, NajouaUNSPECIFIEDorcid.org/0000-0002-0165-3324UNSPECIFIED
Boyden, Steven E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oda, HirotsuguUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wood, Geryl M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stone, Deborah L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chau, DiepUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liu, LinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stoffels, MoniqueUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kratina, TobiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lawlor, Kate E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zaal, Kristien J. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoffmann, Patrycja M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Etemadi, NimaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shield-Artin, KristyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Biben, ChristineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tsai, Wanxia LiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blake, Mary D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kuehn, Hye SunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yang, DanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Anderton, HollyUNSPECIFIEDorcid.org/0000-0003-3913-9686UNSPECIFIED
Silke, NatashaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wachsmuth, LaurensUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zheng, LixinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moura, Natalia SampaioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beck, David B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gutierrez-Cruz, GustavoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ombrello, Amanda K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pinto-Patarroyo, Gineth P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kueh, Andrew J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herold, Marco J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hall, CathrineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, HongyingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chae, Jae JinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dmitrieva, Natalia I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McKenzie, MarkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Light, AmandaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barham, Beverly K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jones, AnneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Romeo, Tina M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhou, QingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aksentijevich, IvonaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mullikin, James C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gross, Andrew J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shum, Anthony K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hawkins, Edwin D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Masters, Seth L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lenardo, Michael J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boehm, ManfredUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rosenzweig, Sergio D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pasparakis, ManolisUNSPECIFIEDorcid.org/0000-0002-9870-0966UNSPECIFIED
Voss, Anne K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gadina, MassimoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kastner, Daniel L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Silke, JohnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-349344
DOI: 10.1038/s41586-019-1828-5
Journal or Publication Title: Nature
Volume: 577
Number: 7788
Page Range: S. 103 - 123
Date: 2020
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 1476-4687
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
DOMAIN KINASE RIP; CELL-DEATH; PSEUDOKINASE MLKL; NECROPTOSIS; ACTIVATION; PHOSPHORYLATION; INFLAMMATION; EXPRESSION; RECEPTORS; LETHALITYMultiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/34934

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item