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

作者：Joanne M. Hildebrand, Maria Kauppi, Ian J. Majewski, Zikou Liu, Allison Cox, Sanae Miyake, Emma J. Petrie, Michael A. Silk, Zhixiu Li, Maria C. Tanzer, Gabriela Brumatti, Samuel N. Young, Cathrine M. Hall, Sarah E. Garnish, Jason E. Corbin, Michael D. Stutz, Ladina Di Rago, Pradnya Gangatirkar, Emma C. Josefsson, Kristin A. Rigbye, Holly Anderton, James A. Rickard, Anne Tripaydonis, Julie M. Sheridan, Thomas S. Scerri, Victoria E. Jackson, Peter E. Czabotar, Jian‐Guo Zhang, Leila N. Varghese, Cody C. Allison, Marc Pellegrini, Gillian M. Tannahill, Esme C. Hatchell, Tracy A. Willson, Dina Stockwell, Carolyn A. de Graaf, Janelle E. Collinge, Adrienne A. Hilton, Natasha Silke, Sukhdeep Kaur Spall, Diep Chau, Vicki Athanasopoulos, Donald Metcalf, Ronald M. Laxer, Alexander G. Bassuk, Benjamin W. Darbro, Maria A. Fiatarone Singh, Nicole Vlahovich, David Hughes, Maria Kozlovskaia, David Benjamin Ascher, Klaus Warnatz, Nils Venhoff, Jens Thiel, Christine Biben, Stefan Blum, John D. Reveille, Michael S. Hildebrand, Carola G. Vinuesa, Pamela McCombe, Matthew A. Brown, Benjamin T. Kile, Catriona McLean, Melanie Bahlo, Seth Lucian Masters, Hiroyasu Nakano, Polly J. Ferguson, James M. Murphy, Warren S. Alexander, John Silke · 发表于：Nature Communications · 年份：2020 · DOI：10.1038/s41467-020-16819-z · 被引用次数：96 · 研究领域：interferon and immune responses、Viral Infections and Immunology Research、Cell death mechanisms and regulation

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 ofMlklD139Vhomozygotes 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 humanMLKLpolymorphisms 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).