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A missense mutation in the MLKL brace region promotes lethal neonatal inflammation and hematopoietic dysfunction

Author

Listed:
  • Joanne M. Hildebrand

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Maria Kauppi

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Ian J. Majewski

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Zikou Liu

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Allison J. Cox

    (University of Iowa Carver College of Medicine)

  • Sanae Miyake

    (Toho University School of Medicine, Ota-ku)

  • Emma J. Petrie

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Michael A. Silk

    (University of Melbourne
    Baker Heart and Diabetes Institute)

  • Zhixiu Li

    (Queensland University of Technology (QUT) at Translational Research Institute)

  • Maria C. Tanzer

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne
    Max Planck Institute of Biochemistry)

  • Gabriela Brumatti

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Samuel N. Young

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Cathrine Hall

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Sarah E. Garnish

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Jason Corbin

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Michael D. Stutz

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne
    Oregon Health and Science University)

  • Ladina Rago

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Pradnya Gangatirkar

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Emma C. Josefsson

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Kristin Rigbye

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne
    Murdoch Children’s Research Institute)

  • Holly Anderton

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • James A. Rickard

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne
    The Royal Melbourne Hospital)

  • Anne Tripaydonis

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne
    The Royal Melbourne Hospital)

  • Julie Sheridan

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Thomas S. Scerri

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Victoria E. Jackson

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Peter E. Czabotar

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Jian-Guo Zhang

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Leila Varghese

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne
    Ludwig Institute for Cancer Research and de Duve Institute)

  • Cody C. Allison

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Marc Pellegrini

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Gillian M. Tannahill

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne
    GSK Medicines Research Centre)

  • Esme C. Hatchell

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Tracy A. Willson

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Dina Stockwell

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Carolyn A. Graaf

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Janelle Collinge

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Adrienne Hilton

    (The Walter and Eliza Hall Institute of Medical Research)

  • Natasha Silke

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Sukhdeep K. Spall

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Diep Chau

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne
    CSL Limited)

  • Vicki Athanasopoulos

    (Australian National University
    Shanghai Jiao Tong University)

  • Donald Metcalf

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Ronald M. Laxer

    (The Hospital for Sick Children and the University of Toronto)

  • Alexander G. Bassuk

    (University of Iowa Carver College of Medicine
    University of Iowa Carver College of Medicine and the Iowa Neuroscience Institute)

  • Benjamin W. Darbro

    (University of Iowa Carver College of Medicine)

  • Maria A. Fiatarone Singh

    (University of Sydney)

  • Nicole Vlahovich

    (Australian Institute of Sport)

  • David Hughes

    (Australian Institute of Sport)

  • Maria Kozlovskaia

    (Australian Institute of Sport
    University of Canberra)

  • David B. Ascher

    (University of Melbourne
    Baker Heart and Diabetes Institute)

  • Klaus Warnatz

    (Medical Center –University of Freiburg, Faculty of Medicine
    Medical Center –University of Freiburg, Faculty of Medicine)

  • Nils Venhoff

    (Medical Center –University of Freiburg, Faculty of Medicine)

  • Jens Thiel

    (Medical Center –University of Freiburg, Faculty of Medicine)

  • Christine Biben

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Stefan Blum

    (Princess Alexandra Hospital)

  • John Reveille

    (Memorial Hermann Texas Medical Centre)

  • Michael S. Hildebrand

    (University of Melbourne, Austin Health
    Royal Children’s Hospital)

  • Carola G. Vinuesa

    (Australian National University
    Shanghai Jiao Tong University)

  • Pamela McCombe

    (Royal Brisbane & Women’s Hospital)

  • Matthew A. Brown

    (Queensland University of Technology (QUT) at Translational Research Institute
    NIHR Biomedical Research Centre, Kings College)

  • Benjamin T. Kile

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne
    The University of Adelaide)

  • Catriona McLean

    (The Alfred Hospital)

  • Melanie Bahlo

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Seth L. Masters

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Hiroyasu Nakano

    (Toho University School of Medicine, Ota-ku)

  • Polly J. Ferguson

    (University of Iowa Carver College of Medicine)

  • James M. Murphy

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Warren S. Alexander

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • John Silke

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

Abstract

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, MlklD139V, 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 MlklD139V 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).

Suggested Citation

  • Joanne M. Hildebrand & Maria Kauppi & Ian J. Majewski & Zikou Liu & Allison J. Cox & Sanae Miyake & Emma J. Petrie & Michael A. Silk & Zhixiu Li & Maria C. Tanzer & Gabriela Brumatti & Samuel N. Young, 2020. "A missense mutation in the MLKL brace region promotes lethal neonatal inflammation and hematopoietic dysfunction," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16819-z
    DOI: 10.1038/s41467-020-16819-z
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    Cited by:

    1. Yanxiang Meng & Katherine A. Davies & Cheree Fitzgibbon & Samuel N. Young & Sarah E. Garnish & Christopher R. Horne & Cindy Luo & Jean-Marc Garnier & Lung-Yu Liang & Angus D. Cowan & Andre L. Samson &, 2021. "Human RIPK3 maintains MLKL in an inactive conformation prior to cell death by necroptosis," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    2. Sarah E. Garnish & Katherine R. Martin & Maria Kauppi & Victoria E. Jackson & Rebecca Ambrose & Vik Ven Eng & Shene Chiou & Yanxiang Meng & Daniel Frank & Emma C. Tovey Crutchfield & Komal M. Patel & , 2023. "A common human MLKL polymorphism confers resistance to negative regulation by phosphorylation," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Yanxiang Meng & Sarah E. Garnish & Katherine A. Davies & Katrina A. Black & Andrew P. Leis & Christopher R. Horne & Joanne M. Hildebrand & Hanadi Hoblos & Cheree Fitzgibbon & Samuel N. Young & Toby Di, 2023. "Phosphorylation-dependent pseudokinase domain dimerization drives full-length MLKL oligomerization," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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