Nature Communications (Sep 2023)
A common human MLKL polymorphism confers resistance to negative regulation by phosphorylation
- 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,
- Annette V. Jacobsen,
- Georgia K. Atkin-Smith,
- Ladina Di Rago,
- Marcel Doerflinger,
- Christopher R. Horne,
- Cathrine Hall,
- Samuel N. Young,
- Matthew Cook,
- Vicki Athanasopoulos,
- Carola G. Vinuesa,
- Kate E. Lawlor,
- Ian P. Wicks,
- Gregor Ebert,
- Ashley P. Ng,
- Charlotte A. Slade,
- Jaclyn S. Pearson,
- André L. Samson,
- John Silke,
- James M. Murphy,
- Joanne M. Hildebrand
Affiliations
- Sarah E. Garnish
- The Walter and Eliza Hall Institute
- Katherine R. Martin
- The Walter and Eliza Hall Institute
- Maria Kauppi
- The Walter and Eliza Hall Institute
- Victoria E. Jackson
- The Walter and Eliza Hall Institute
- Rebecca Ambrose
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research
- Vik Ven Eng
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research
- Shene Chiou
- The Walter and Eliza Hall Institute
- Yanxiang Meng
- The Walter and Eliza Hall Institute
- Daniel Frank
- The Walter and Eliza Hall Institute
- Emma C. Tovey Crutchfield
- The Walter and Eliza Hall Institute
- Komal M. Patel
- The Walter and Eliza Hall Institute
- Annette V. Jacobsen
- The Walter and Eliza Hall Institute
- Georgia K. Atkin-Smith
- The Walter and Eliza Hall Institute
- Ladina Di Rago
- The Walter and Eliza Hall Institute
- Marcel Doerflinger
- The Walter and Eliza Hall Institute
- Christopher R. Horne
- The Walter and Eliza Hall Institute
- Cathrine Hall
- The Walter and Eliza Hall Institute
- Samuel N. Young
- The Walter and Eliza Hall Institute
- Matthew Cook
- Centre for Personalised Immunology and Canberra Clinical Genomics, Australian National University
- Vicki Athanasopoulos
- Department of Immunology and Infection, John Curtin School of Medical Research, Australian National University
- Carola G. Vinuesa
- Centre for Personalised Immunology and Canberra Clinical Genomics, Australian National University
- Kate E. Lawlor
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research
- Ian P. Wicks
- The Walter and Eliza Hall Institute
- Gregor Ebert
- Institute of Virology, Technical University of Munich/Helmholtz Munich
- Ashley P. Ng
- The Walter and Eliza Hall Institute
- Charlotte A. Slade
- The Walter and Eliza Hall Institute
- Jaclyn S. Pearson
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research
- André L. Samson
- The Walter and Eliza Hall Institute
- John Silke
- The Walter and Eliza Hall Institute
- James M. Murphy
- The Walter and Eliza Hall Institute
- Joanne M. Hildebrand
- The Walter and Eliza Hall Institute
- DOI
- https://doi.org/10.1038/s41467-023-41724-6
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 1 – 17
Abstract
Abstract Across the globe, 2-3% of humans carry the p.Ser132Pro single nucleotide polymorphism in MLKL, the terminal effector protein of the inflammatory form of programmed cell death, necroptosis. Here we show that this substitution confers a gain in necroptotic function in human cells, with more rapid accumulation of activated MLKLS132P in biological membranes and MLKLS132P overriding pharmacological and endogenous inhibition of MLKL. In mouse cells, the equivalent Mlkl S131P mutation confers a gene dosage dependent reduction in sensitivity to TNF-induced necroptosis in both hematopoietic and non-hematopoietic cells, but enhanced sensitivity to IFN-β induced death in non-hematopoietic cells. In vivo, Mlkl S131P homozygosity reduces the capacity to clear Salmonella from major organs and retards recovery of hematopoietic stem cells. Thus, by dysregulating necroptosis, the S131P substitution impairs the return to homeostasis after systemic challenge. Present day carriers of the MLKL S132P polymorphism may be the key to understanding how MLKL and necroptosis modulate the progression of complex polygenic human disease.
