title: TRAF2 regulates TNF and NF-κB signalling to suppress apoptosis and skin inflammation independently of Sphingosine kinase 1.
abstract: TRAF2 is a component of TNF superfamily signalling complexes and plays an essential role in the regulation and homeostasis of immune cells. TRAF2 deficient mice die around birth, therefore its role in adult tissues is not well-explored. Furthermore, the role of the TRAF2 RING is controversial. It has been claimed that the atypical TRAF2 RING cannot function as a ubiquitin E3 ligase but counterclaimed that TRAF2 RING requires a co-factor, sphingosine-1-phosphate, that is generated by the enzyme sphingosine kinase 1, to function as an E3 ligase. Keratinocyte-specific deletion of Traf2, but not Sphk1 deficiency, disrupted TNF mediated NF-κB and MAP kinase signalling and caused epidermal hyperplasia and psoriatic skin inflammation. This inflammation was driven by TNF, cell death, non-canonical NF-κB and the adaptive immune system, and might therefore represent a clinically relevant model of psoriasis. TRAF2 therefore has essential tissue specific functions that do not overlap with those of Sphk1.
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Australia.|Olivia Newton-John Cancer Research Institute, Heidelberg, Australia.|School of Cancer Medicine, La Trobe University, Heidelberg, Australia.
authors.forename: Nima
authors.identifier: http://orcid.org/0000-0002-7137-1373
authors.initials: N
authors.lastname: Etemadi
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Chopin
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Australia.
authors.forename: Holly
authors.initials: H
authors.lastname: Anderton
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Australia.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Tanzer
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Australia.
authors.forename: James A
authors.initials: JA
authors.lastname: Rickard
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
authors.forename: Waruni
authors.initials: W
authors.lastname: Abeysekera
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
authors.forename: Cathrine
authors.initials: C
authors.lastname: Hall
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
authors.forename: Sukhdeep K
authors.initials: SK
authors.lastname: Spall
authors.affiliation: Center for Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia.
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.affiliation: Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, United States.
authors.forename: Yuquan
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, United States.
authors.forename: Timothy
authors.initials: T
authors.lastname: Hla
authors.affiliation: Centre for Cancer Biology, SA Pathology, Adelaide, Australia.
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Pitson
authors.affiliation: Centre for Cancer Biology, SA Pathology, Adelaide, Australia.
authors.forename: Claudine S
authors.initials: CS
authors.lastname: Bonder
authors.affiliation: Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
authors.forename: Wendy Wei-Lynn
authors.initials: WW
authors.lastname: Wong
authors.affiliation: Olivia Newton-John Cancer Research Institute, Heidelberg, Australia.|School of Cancer Medicine, La Trobe University, Heidelberg, Australia.
authors.forename: Matthias
authors.initials: M
authors.lastname: Ernst
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.|Department of Mathematics and Statistics, University of Melbourne, Parkville, Australia.
authors.forename: Gordon K
authors.identifier: http://orcid.org/0000-0001-9221-2892
authors.initials: GK
authors.lastname: Smyth
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Australia.
authors.forename: David L
authors.initials: DL
authors.lastname: Vaux
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Australia.
authors.forename: Stephen L
authors.identifier: http://orcid.org/0000-0002-0020-6637
authors.initials: SL
authors.lastname: Nutt
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Australia.
authors.forename: Ueli
authors.initials: U
authors.lastname: Nachbur
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Silke
mesh_terms: D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D007249:Inflammation / Q000473:pathology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D011565:Psoriasis / Q000473:pathology; D015398:Signal Transduction; D012867:Skin / Q000473:pathology*; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D016328:NF-kappa B; D017853:Phosphotransferases (Alcohol Group Acceptor); D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; D000099157:Sphingosine Kinase
keywords: NF-kB; TNF; apoptosis; biochemistry; immunology; inflammation; mouse; psoriasis