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TRAF2 regulates TNF and NF-κB signalling to suppress apoptosis and skin inflammation independently of Sphingosine kinase-1


Etemadi, N; Chopin, M; Anderton, H; Tanzer, M C; Rickard, J A; Abeysekra, W; Hall, C; Spall, S K; Wang, B; Xiong, Y; HLa, T; Pitson, S M; Bonder, C S; Wong, W W; Ernst, M; Smyth, G K; Vaux, D L; Nutt, S L; Nachbur, U; Silke, J (2015). TRAF2 regulates TNF and NF-κB signalling to suppress apoptosis and skin inflammation independently of Sphingosine kinase-1. eLife, 4:e10592.

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.

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.

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Contributors:Walter and Eliza Hall Institute of Medical Research, Parkville, Australia., 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., Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, United States., Centre for Cancer Biology, SA Pathology, Adelaide, Australia., Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland., Olivia Newton-John Cancer Research Institute, Heidelberg, Australia., Bioinformatics, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Experimental Immunology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:23 December 2015
Deposited On:07 Jan 2016 08:41
Last Modified:05 Aug 2017 11:28
Publisher:eLife Sciences Publications Ltd.
ISSN:2050-084X
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.7554/eLife.10592
PubMed ID:26701909

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