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

• DOI: 10.7554/elife.10592
• Publication Date: 2015-12-22T12:41:18Z
• Authors: 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
• Keywords: 0301 basic medicine; 570; QH301-705.5; Science; TNF; 610 Medicine & health; Apoptosis; 10263 Institute of Experimental Immunology; Biochemistry; Mice; 03 medical and health sciences; immune cells; 1300 General Biochemistry, Genetics and Molecular Biology; 2400 General Immunology and Microbiology; Animals; Psoriasis; Sphingosine kinase 1; NF-kB; Biology (General); Biology; Skin; Inflammation; Tumor Necrosis Factor-alpha; Q; apoptosis; R; NF-kappa B; 2800 General Neuroscience; psoriasis; TNF Receptor-Associated Factor 2; 3. Good health; Disease Models, Animal; Phosphotransferases (Alcohol Group Acceptor); TRAF2; inflammation; 570 Life sciences; biology; Medicine; Signal Transduction

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.