Format

Send to

Choose Destination
Nature. 2020 Jan;577(7788):103-108. doi: 10.1038/s41586-019-1828-5. Epub 2019 Dec 11.

Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease.

Author information

1
The Walter and Eliza Hall Institute, Parkville, Victoria, Australia. lalaoui@wehi.edu.au.
2
Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia. lalaoui@wehi.edu.au.
3
Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. steven.boyden@genetics.utah.edu.
4
Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
5
The Walter and Eliza Hall Institute, Parkville, Victoria, Australia.
6
Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
7
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
8
Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia.
9
Light Imaging Section, Office of Science and Technology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
10
Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
11
Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
12
Translational Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
13
Institute for Genetics & Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
14
Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany.
15
Molecular Development of the Immune System Section, Laboratory of Immune System Biology; Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
16
Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
17
NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
18
Division of Rheumatology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
19
Division of Pulmonary and Critical Care, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
20
Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. kastnerd@mail.nih.gov.
21
The Walter and Eliza Hall Institute, Parkville, Victoria, Australia. silke@wehi.edu.au.
22
Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia. silke@wehi.edu.au.

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.

PMID:
31827281
PMCID:
PMC6930849
[Available on 2020-06-11]
DOI:
10.1038/s41586-019-1828-5

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center