Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease

Najoua Lalaoui (), Steven E. Boyden (), Hirotsugu Oda, Geryl M. Wood, Deborah L. Stone, Diep Chau, Lin Liu, Monique Stoffels, Tobias Kratina, Kate E. Lawlor, Kristien J. M. Zaal, Patrycja M. Hoffmann, Nima Etemadi, Kristy Shield-Artin, Christine Biben, Wanxia Li Tsai, Mary D. Blake, Hye Sun Kuehn, Dan Yang, Holly Anderton, Natasha Silke, Laurens Wachsmuth, Lixin Zheng, Natalia Sampaio Moura, David B. Beck, Gustavo Gutierrez-Cruz, Amanda K. Ombrello, Gineth P. Pinto-Patarroyo, Andrew J. Kueh, Marco J. Herold, Cathrine Hall, Hongying Wang, Jae Jin Chae, Natalia I. Dmitrieva, Mark McKenzie, Amanda Light, Beverly K. Barham, Anne Jones, Tina M. Romeo, Qing Zhou, Ivona Aksentijevich, James C. Mullikin, Andrew J. Gross, Anthony K. Shum, Edwin D. Hawkins, Seth L. Masters, Michael J. Lenardo, Manfred Boehm, Sergio D. Rosenzweig, Manolis Pasparakis, Anne K. Voss, Massimo Gadina, Daniel L. Kastner () and John Silke ()
Additional contact information
Najoua Lalaoui: The Walter and Eliza Hall Institute
Steven E. Boyden: National Institutes of Health
Hirotsugu Oda: National Institutes of Health
Geryl M. Wood: National Institutes of Health
Deborah L. Stone: National Institutes of Health
Diep Chau: The Walter and Eliza Hall Institute
Lin Liu: The Walter and Eliza Hall Institute
Monique Stoffels: National Institutes of Health
Tobias Kratina: The Walter and Eliza Hall Institute
Kate E. Lawlor: Hudson Institute of Medical Research
Kristien J. M. Zaal: National Institutes of Health
Patrycja M. Hoffmann: National Institutes of Health
Nima Etemadi: The Walter and Eliza Hall Institute
Kristy Shield-Artin: The Walter and Eliza Hall Institute
Christine Biben: The Walter and Eliza Hall Institute
Wanxia Li Tsai: National Institutes of Health
Mary D. Blake: National Institutes of Health
Hye Sun Kuehn: National Institutes of Health
Dan Yang: National Institutes of Health
Holly Anderton: The Walter and Eliza Hall Institute
Natasha Silke: The Walter and Eliza Hall Institute
Laurens Wachsmuth: University of Cologne
Lixin Zheng: National Institutes of Health
Natalia Sampaio Moura: National Institutes of Health
David B. Beck: National Institutes of Health
Gustavo Gutierrez-Cruz: National Institutes of Health
Amanda K. Ombrello: National Institutes of Health
Gineth P. Pinto-Patarroyo: National Institutes of Health
Andrew J. Kueh: The Walter and Eliza Hall Institute
Marco J. Herold: The Walter and Eliza Hall Institute
Cathrine Hall: The Walter and Eliza Hall Institute
Hongying Wang: National Institutes of Health
Jae Jin Chae: National Institutes of Health
Natalia I. Dmitrieva: National Institutes of Health
Mark McKenzie: The Walter and Eliza Hall Institute
Amanda Light: The Walter and Eliza Hall Institute
Beverly K. Barham: National Institutes of Health
Anne Jones: National Institutes of Health
Tina M. Romeo: National Institutes of Health
Qing Zhou: National Institutes of Health
Ivona Aksentijevich: National Institutes of Health
James C. Mullikin: National Institutes of Health
Andrew J. Gross: University of California San Francisco
Anthony K. Shum: University of California San Francisco
Edwin D. Hawkins: The Walter and Eliza Hall Institute
Seth L. Masters: The Walter and Eliza Hall Institute
Michael J. Lenardo: National Institutes of Health
Manfred Boehm: National Institutes of Health
Sergio D. Rosenzweig: National Institutes of Health
Manolis Pasparakis: University of Cologne
Anne K. Voss: The Walter and Eliza Hall Institute
Massimo Gadina: National Institutes of Health
Daniel L. Kastner: National Institutes of Health
John Silke: The Walter and Eliza Hall Institute

Nature, 2020, vol. 577, issue 7788, 103-108

Abstract: 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 Ripk1D325A mutant mouse strain. Whereas Ripk1−/− mice died postnatally from systemic inflammation, Ripk1D325A/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 Ripk1D325A/D325A embryonic lethality, although the mice died before weaning from multi-organ inflammation in a RIPK3-dependent manner. Consistently, Ripk1D325A/D325A and Ripk1D325A/+ cells were hypersensitive to RIPK3-dependent TNF-induced apoptosis and necroptosis. Heterozygous Ripk1D325A/+ 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.

Date: 2020
References: Add references at CitEc
Citations: View citations in EconPapers (3)

Downloads: (external link)
https://www.nature.com/articles/s41586-019-1828-5 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:577:y:2020:i:7788:d:10.1038_s41586-019-1828-5

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-019-1828-5

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().