title: TNFR1-dependent cell death drives inflammation in Sharpin-deficient mice.
abstract: 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.
authors.affiliation: Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
authors.forename: James A
authors.initials: JA
authors.lastname: Rickard
authors.affiliation: Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
authors.forename: Holly
authors.initials: H
authors.lastname: Anderton
authors.affiliation: Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
authors.forename: Nima
authors.initials: N
authors.lastname: Etemadi
authors.affiliation: Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
authors.forename: Ueli
authors.initials: U
authors.lastname: Nachbur
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation, University College London, London, United Kingdom.
authors.forename: Maurice
authors.initials: M
authors.lastname: Darding
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation, University College London, London, United Kingdom.
authors.forename: Nieves
authors.initials: N
authors.lastname: Peltzer
authors.affiliation: Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
authors.forename: Najoua
authors.initials: N
authors.lastname: Lalaoui
authors.affiliation: Department of Medical Biology, University of Melbourne, Parkville, Australia.
authors.forename: Kate E
authors.initials: KE
authors.lastname: Lawlor
authors.affiliation: Department of Medical Biology, University of Melbourne, Parkville, Australia.
authors.forename: Hannah
authors.initials: H
authors.lastname: Vanyai
authors.affiliation: Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
authors.forename: Cathrine
authors.initials: C
authors.lastname: Hall
authors.affiliation: Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
authors.forename: Aleks
authors.initials: A
authors.lastname: Bankovacki
authors.affiliation: Department of Biochemistry, La Trobe University, Bundoora, Australia.
authors.forename: Lahiru
authors.initials: L
authors.lastname: Gangoda
authors.affiliation: Department of Immunology, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
authors.forename: Wendy Wei-Lynn
authors.initials: WW
authors.lastname: Wong
authors.affiliation: Department of Medical Biology, University of Melbourne, Parkville, Australia.
authors.forename: Jason
authors.initials: J
authors.lastname: Corbin
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, United States.
authors.forename: Chunzi
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, United States.
authors.forename: Edward S
authors.initials: ES
authors.lastname: Mocarski
authors.affiliation: Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
authors.forename: James M
authors.initials: JM
authors.lastname: Murphy
authors.affiliation: Department of Medical Biology, University of Melbourne, Parkville, Australia.
authors.forename: Warren S
authors.initials: WS
authors.lastname: Alexander
authors.affiliation: Department of Medical Biology, University of Melbourne, Parkville, Australia.
authors.forename: Anne K
authors.initials: AK
authors.lastname: Voss
authors.affiliation: Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
authors.forename: David L
authors.initials: DL
authors.lastname: Vaux
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, United States.
authors.forename: William J
authors.initials: WJ
authors.lastname: Kaiser
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation, University College London, London, United Kingdom.
authors.forename: Henning
authors.initials: H
authors.lastname: Walczak
authors.affiliation: Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Silke
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002908:Chronic Disease; D019610:Cytoprotection / Q000187:drug effects; D003872:Dermatitis / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006579:Heterozygote; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology*; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D009419:Nerve Tissue Proteins; D017472:Receptors, Interleukin-1; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; C425287:sharpin; C492590:Rnf31 protein, mouse; D044767:Ubiquitin-Protein Ligases; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; D053148:Caspase 3; D053181:Caspase 8
keywords: LUBAC; TNF signaling; apoptosis; cell biology; dermatitis; developmental biology; inflammation; mouse; stem cells; ubiquitin