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A missense mutation in the MLKL brace region promotes lethal neonatal inflammation and hematopoietic dysfunction.
Hildebrand, Joanne M; Kauppi, Maria; Majewski, Ian J; Liu, Zikou; Cox, Allison J; Miyake, Sanae; Petrie, Emma J; Silk, Michael A; Li, Zhixiu; Tanzer, Maria C; Brumatti, Gabriela; Young, Samuel N; Hall, Cathrine; Garnish, Sarah E; Corbin, Jason; Stutz, Michael D; Di Rago, Ladina; Gangatirkar, Pradnya; Josefsson, Emma C; Rigbye, Kristin; Anderton, Holly; Rickard, James A; Tripaydonis, Anne; Sheridan, Julie; Scerri, Thomas S; Jackson, Victoria E; Czabotar, Peter E; Zhang, Jian-Guo; Varghese, Leila; Allison, Cody C; Pellegrini, Marc; Tannahill, Gillian M; Hatchell, Esme C; Willson, Tracy A; Stockwell, Dina; de Graaf, Carolyn A; Collinge, Janelle; Hilton, Adrienne; Silke, Natasha; Spall, Sukhdeep K; Chau, Diep; Athanasopoulos, Vicki; Metcalf, Donald; Laxer, Ronald M; Bassuk, Alexander G; Darbro, Benjamin W; Fiatarone Singh, Maria A; Vlahovich, Nicole; Hughes, David; Kozlovskaia, Maria.
Afiliação
  • Hildebrand JM; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia. jhildebrand@wehi.edu.au.
  • Kauppi M; Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia. jhildebrand@wehi.edu.au.
  • Majewski IJ; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
  • Liu Z; Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia.
  • Cox AJ; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
  • Miyake S; Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia.
  • Petrie EJ; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
  • Silk MA; Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia.
  • Li Z; Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.
  • Tanzer MC; Department of Biochemistry, Toho University School of Medicine, Ota-ku, Tokyo, 143-8540, Japan.
  • Brumatti G; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
  • Young SN; Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia.
  • Hall C; Department of Biochemistry and Molecular Biology, Bio21 Institute, University of Melbourne, Melbourne, VIC, 3052, Australia.
  • Garnish SE; Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.
  • Corbin J; Translational Genomics Group, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology (QUT) at Translational Research Institute, Brisbane, Australia.
  • Stutz MD; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
  • Di Rago L; Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia.
  • Gangatirkar P; Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, 82152, Germany.
  • Josefsson EC; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
  • Rigbye K; Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia.
  • Anderton H; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
  • Rickard JA; Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia.
  • Tripaydonis A; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
  • Sheridan J; Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia.
  • Scerri TS; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
  • Jackson VE; Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia.
  • Czabotar PE; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
  • Zhang JG; Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia.
  • Varghese L; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
  • Allison CC; Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia.
  • Pellegrini M; Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR, 97006, USA.
  • Tannahill GM; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
  • Hatchell EC; Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia.
  • Willson TA; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
  • Stockwell D; Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia.
  • de Graaf CA; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
  • Collinge J; Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia.
  • Hilton A; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
  • Silke N; Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia.
  • Spall SK; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, VIC, 3052, Australia.
  • Chau D; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
  • Athanasopoulos V; Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia.
  • Metcalf D; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
  • Laxer RM; Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia.
  • Bassuk AG; The Royal Melbourne Hospital, Melbourne, VIC, 3050, Australia.
  • Darbro BW; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
  • Fiatarone Singh MA; Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia.
  • Vlahovich N; The Royal Melbourne Hospital, Melbourne, VIC, 3050, Australia.
  • Hughes D; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
  • Kozlovskaia M; Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia.
Nat Commun ; 11(1): 3150, 2020 06 19.
Article em En | MEDLINE | ID: mdl-32561755
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).
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas Quinases / Células-Tronco Hematopoéticas / Necroptose / Sistema Hematopoético Limite: Animals / Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas Quinases / Células-Tronco Hematopoéticas / Necroptose / Sistema Hematopoético Limite: Animals / Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article