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

Nima Etemadi; Michael Chopin; Holly Anderton; Maria C Tanzer; James A Rickard; Waruni Abeysekera; Cathrine Hall; Sukhdeep K Spall; Bing Wang; Yuquan Xiong; Timothy Hla; Stuart M Pitson; Claudine S Bonder; Wendy Wei-Lynn Wong; Matthias Ernst; Gordon K Smyth; David L Vaux; Stephen L Nutt; Ueli Nachbur; John Silke

doi:10.7554/eLife.10592

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

Elife. 2015 Dec 23:4:e10592. doi: 10.7554/eLife.10592.

Authors

Nima Etemadi^{1

2

3

4}, Michael Chopin^{1

2}, Holly Anderton^{1

2}, Maria C Tanzer^{1

2}, James A Rickard^{1

2}, Waruni Abeysekera¹, Cathrine Hall¹, Sukhdeep K Spall¹, Bing Wang⁵, Yuquan Xiong⁶, Timothy Hla⁶, Stuart M Pitson⁷, Claudine S Bonder⁷, Wendy Wei-Lynn Wong⁸, Matthias Ernst^{3

4}, Gordon K Smyth^{1

9}, David L Vaux^{1

2}, Stephen L Nutt^{1

2}, Ueli Nachbur^{1

2}, John Silke^{1

2}

Affiliations

¹ Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
² Department of Medical Biology, University of Melbourne, Parkville, Australia.
³ Olivia Newton-John Cancer Research Institute, Heidelberg, Australia.
⁴ School of Cancer Medicine, La Trobe University, Heidelberg, Australia.
⁵ 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.
⁶ Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, United States.
⁷ Centre for Cancer Biology, SA Pathology, Adelaide, Australia.
⁸ Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
⁹ Department of Mathematics and Statistics, University of Melbourne, Parkville, Australia.

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.

Keywords: NF-kB; TNF; apoptosis; biochemistry; immunology; inflammation; mouse; psoriasis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis*
Disease Models, Animal
Inflammation / pathology*
Mice
NF-kappa B / metabolism*
Phosphotransferases (Alcohol Group Acceptor) / metabolism*
Psoriasis / pathology
Signal Transduction
Skin / pathology*
TNF Receptor-Associated Factor 2 / metabolism*
Tumor Necrosis Factor-alpha / metabolism

Substances

NF-kappa B
TNF Receptor-Associated Factor 2
Tumor Necrosis Factor-alpha
Phosphotransferases (Alcohol Group Acceptor)
sphingosine kinase

Abstract

Publication types

MeSH terms

Substances

Grants and funding