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TNFR1-dependent cell death drives inflammation in Sharpin-deficient mice.
Journal article

TNFR1-dependent cell death drives inflammation in Sharpin-deficient mice.

  • Rickard JA Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
  • Anderton H Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
  • Etemadi N Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
  • Nachbur U Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
  • Darding M Centre for Cell Death, Cancer, and Inflammation, University College London, London, United Kingdom.
  • Peltzer N Centre for Cell Death, Cancer, and Inflammation, University College London, London, United Kingdom.
  • Lalaoui N Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
  • Lawlor KE Department of Medical Biology, University of Melbourne, Parkville, Australia.
  • Vanyai H Department of Medical Biology, University of Melbourne, Parkville, Australia.
  • Hall C Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
  • Bankovacki A Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
  • Gangoda L Department of Biochemistry, La Trobe University, Bundoora, Australia.
  • Wong WW Department of Immunology, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
  • Corbin J Department of Medical Biology, University of Melbourne, Parkville, Australia.
  • Huang C Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, United States.
  • Mocarski ES Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, United States.
  • Murphy JM Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
  • Alexander WS Department of Medical Biology, University of Melbourne, Parkville, Australia.
  • Voss AK Department of Medical Biology, University of Melbourne, Parkville, Australia.
  • Vaux DL Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
  • Kaiser WJ Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, United States.
  • Walczak H Centre for Cell Death, Cancer, and Inflammation, University College London, London, United Kingdom.
  • Silke J Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
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  • 2014-12-03
Published in:
  • eLife. - 2014
LUBAC
TNF signaling
apoptosis
cell biology
dermatitis
developmental biology
inflammation
mouse
stem cells
ubiquitin
Animals
Caspase 3
Caspase 8
Cell Death
Cells, Cultured
Chronic Disease
Cytoprotection
Dermatitis
Fibroblasts
Heterozygote
Inflammation
Keratinocytes
Liver
Macrophages
Mice, Inbred C57BL
Myeloid Cells
Nerve Tissue Proteins
Receptor-Interacting Protein Serine-Threonine Kinases
Receptors, Interleukin-1
Receptors, Tumor Necrosis Factor, Type I
Receptors, Tumor Necrosis Factor, Type II
Spleen
Tumor Necrosis Factor-alpha
Ubiquitin-Protein Ligases
Ubiquitination
English SHARPIN regulates immune signaling and contributes to full transcriptional activity and prevention of cell death in response to TNF in vitro. The inactivating mouse Sharpin cpdm mutation causes TNF-dependent multi-organ inflammation, characterized by dermatitis, liver inflammation, splenomegaly, and loss of Peyer's patches. TNF-dependent cell death has been proposed to cause the inflammatory phenotype and consistent with this we show Tnfr1, but not Tnfr2, deficiency suppresses the phenotype (and it does so more efficiently than Il1r1 loss). TNFR1-induced apoptosis can proceed through caspase-8 and BID, but reduction in or loss of these players generally did not suppress inflammation, although Casp8 heterozygosity significantly delayed dermatitis. Ripk3 or Mlkl deficiency partially ameliorated the multi-organ phenotype, and combined Ripk3 deletion and Casp8 heterozygosity almost completely suppressed it, even restoring Peyer's patches. Unexpectedly, Sharpin, Ripk3 and Casp8 triple deficiency caused perinatal lethality. These results provide unexpected insights into the developmental importance of SHARPIN.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://sonar.ch/global/documents/147103
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