Nature communications · 2020

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

СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди

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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, Ascher David B, Warnatz Klaus, Venhoff Nils, Thiel Jens, Biben Christine, Blum Stefan, Reveille John, Hildebrand Michael S, Vinuesa Carola G, McCombe Pamela, Brown Matthew A, Kile Benjamin T, McLean Catriona, Bahlo Melanie, Masters Seth L, Nakano Hiroyasu, Ferguson Polly J, Murphy James M, Alexander Warren S, Silke John

Аннотация

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).

Предметные рубрики MeSH

Animals Animals, Newborn Hematopoietic Stem Cells Hematopoietic System Hereditary Autoinflammatory Diseases Humans Inflammation Mice Mutation, Missense Necroptosis Osteomyelitis Protein Kinases

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

Ошибки и ограничения

Аннотация

Предметные рубрики MeSH