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

Nima Etemadi, Michael Chopin, Holly Anderton, Maria C Tanzer, James A Rickard, Waruni Abeysekera, Cathrine M 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

Research output: Contribution to journalArticleResearchpeer-review

43 Citations (Scopus)

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.

Original languageEnglish
Article numbere10592
Number of pages27
JournaleLife
Volume4
Issue numberDECEMBER2015
DOIs
Publication statusPublished - 23 Dec 2015

Cite this

Etemadi, N., Chopin, M., Anderton, H., Tanzer, M. C., Rickard, J. A., Abeysekera, W., Hall, C. M., Spall, S. K., Wang, B., Xiong, Y., Hla, T., Pitson, S. M., Bonder, C. S., Wong, W. W. L., 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. eLife, 4(DECEMBER2015), [e10592]. https://doi.org/10.7554/eLife.10592