期刊
NATURE COMMUNICATIONS
卷 11, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-020-16819-z
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资金
- Australian Phenomics Network (APN)
- Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program
- Australian National Health and Medical Research Council (NHMRC) [1105023, 0541951, 1142669]
- NHMRC [1107149, 1113577, 1058344, 1124735, 1105754, 1172929, 1144282, 1142354, 1099262, 1107425, 1045549, APP1072476, IRIISS 9000587]
- NIH [T32GM008629, T32GM082729-01]
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) at the National Institutes of Health [R01AR059703]
- Marjorie K. Lamb Professorship
- Japan Society for the Promotion of Science, and Scientific Research on Innovative areas [17H04069, 26110003]
- Japan Agency for Medical Research and Development (AMED) through AMED-CREST [JP20gm1210002]
- Private University Research Branding project from a MEXT
- Victorian International Research Scholarship
- Australia Postgraduate Award
- Sylvia and Charles Viertel Foundation
- HHMI-Wellcome International Research Scholarship
- Glaxosmithkline
- Lorenzo and Pamela Galli Charitable Trust
- Sylvia AMP
- Charles Viertel Senior Medical Research Fellowship
- Jack Brockhoff Foundation [JBF 4186]
- Victorian Government Operational Infrastructure Support schemes
- NHMRC Project and Targeted Research grants [1006769, 512672, 512381]
- Department of Industry, Innovation, Science, Research and Tertiary Education Collaborative Research Network
- Diabetes Australia
- Victorian Cancer Agency
- Felton Bequest
- Cancer Australia
- Leukemia Foundation Australia priority grant [PdCCRS 1162023]
- Victoria Cancer Agency (VCA) mid-career fellowship [MCRF 15027]
- Arthritis Research UK [19536, 18797]
- Wellcome Trust [076113]
- Oxford Comprehensive Biomedical Research Centre ankylosing spondylitis chronic disease cohort [A91202]
- Grants-in-Aid for Scientific Research [17H04069, 26110003] Funding Source: KAKEN
- National Health and Medical Research Council of Australia [1105754, 1099262, 1105023, 1107425, 1107149, 1124735, 1142669, 1144282, 1058344, 1142354] Funding Source: NHMRC
MLKL is the essential effector of necroptosis, a form of programmed lytic cell death. We have isolated a mouse strain with a single missense mutation, Mlkl(D139V), that alters the two-helix 'brace' that connects the killer four-helix bundle and regulatory pseudokinase domains. This confers constitutive, RIPK3 independent killing activity to MLKL. Homozygous mutant mice develop lethal postnatal inflammation of the salivary glands and mediastinum. The normal embryonic development of Mlkl(D139V) homozygotes until birth, and the absence of any overt phenotype in heterozygotes provides important in vivo precedent for the capacity of cells to clear activated MLKL. These observations offer an important insight into the potential disease-modulating roles of three common human MLKL polymorphisms that encode amino acid substitutions within or adjacent to the brace region. Compound heterozygosity of these variants is found at up to 12-fold the expected frequency in patients that suffer from a pediatric autoinflammatory disease, chronic recurrent multifocal osteomyelitis (CRMO). Necroptosis is a regulated form of inflammatory cell death driven by activated MLKL. Here, the authors identify a mutation in the brace region that confers constitutive activation, leading to lethal inflammation in homozygous mutant mice and providing insight into human mutations in this region.
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