TRAF2 Regulates TNF and NF-κB Signalling to Suppress Apoptosis and Skin Inflammation Independently of Sphingosine Kinase 1

Overview

Journal Elife

Specialty Biology

Date 2015 Dec 25

PMID 26701909

Citations 48

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

Affiliations

Soon will be listed here.

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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References

Poon I, Chiu Y, Armstrong A, Kinchen J, Juncadella I, Bayliss D . Unexpected link between an antibiotic, pannexin channels and apoptosis. Nature. 2014; 507(7492):329-34. PMC: 4078991. DOI: 10.1038/nature13147. View

Dannappel M, Vlantis K, Kumari S, Polykratis A, Kim C, Wachsmuth L . RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis. Nature. 2014; 513(7516):90-4. PMC: 4206266. DOI: 10.1038/nature13608. View

Panayotova-Dimitrova D, Feoktistova M, Ploesser M, Kellert B, Hupe M, Horn S . cFLIP regulates skin homeostasis and protects against TNF-induced keratinocyte apoptosis. Cell Rep. 2013; 5(2):397-408. DOI: 10.1016/j.celrep.2013.09.035. View

Ha H, Wang H, Pisitkun P, Kim J, Tassi I, Tang W . IL-17 drives psoriatic inflammation via distinct, target cell-specific mechanisms. Proc Natl Acad Sci U S A. 2014; 111(33):E3422-31. PMC: 4143007. DOI: 10.1073/pnas.1400513111. View

Dillon C, Weinlich R, Rodriguez D, Cripps J, Quarato G, Gurung P . RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3. Cell. 2014; 157(5):1189-202. PMC: 4068710. DOI: 10.1016/j.cell.2014.04.018. View

Gardam S, Sierro F, Basten A, Mackay F, Brink R . TRAF2 and TRAF3 signal adapters act cooperatively to control the maturation and survival signals delivered to B cells by the BAFF receptor. Immunity. 2008; 28(3):391-401. DOI: 10.1016/j.immuni.2008.01.009. View

Bonnet M, Preukschat D, Welz P, van Loo G, Ermolaeva M, Bloch W . The adaptor protein FADD protects epidermal keratinocytes from necroptosis in vivo and prevents skin inflammation. Immunity. 2011; 35(4):572-82. DOI: 10.1016/j.immuni.2011.08.014. View

Jabara H, Laouini D, Tsitsikov E, Mizoguchi E, Bhan A, Castigli E . The binding site for TRAF2 and TRAF3 but not for TRAF6 is essential for CD40-mediated immunoglobulin class switching. Immunity. 2002; 17(3):265-76. DOI: 10.1016/s1074-7613(02)00394-1. View

Zarnegar B, Wang Y, Mahoney D, Dempsey P, Cheung H, He J . Noncanonical NF-kappaB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK. Nat Immunol. 2008; 9(12):1371-8. PMC: 2676931. DOI: 10.1038/ni.1676. View

10.

Kohama T, Olivera A, Edsall L, Nagiec M, Dickson R, Spiegel S . Molecular cloning and functional characterization of murine sphingosine kinase. J Biol Chem. 1998; 273(37):23722-8. DOI: 10.1074/jbc.273.37.23722. View

11.

Lee S, Reichlin A, Santana A, Sokol K, Nussenzweig M, Choi Y . TRAF2 is essential for JNK but not NF-kappaB activation and regulates lymphocyte proliferation and survival. Immunity. 1997; 7(5):703-13. DOI: 10.1016/s1074-7613(00)80390-8. View

12.

Rickard J, Anderton H, Etemadi N, Nachbur U, Darding M, Peltzer N . TNFR1-dependent cell death drives inflammation in Sharpin-deficient mice. Elife. 2014; 3. PMC: 4270099. DOI: 10.7554/eLife.03464. View

13.

Gudjonsson J, Johnston A, Dyson M, Valdimarsson H, Elder J . Mouse models of psoriasis. J Invest Dermatol. 2007; 127(6):1292-308. DOI: 10.1038/sj.jid.5700807. View

14.

Murphy J, Czabotar P, Hildebrand J, Lucet I, Zhang J, Alvarez-Diaz S . The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism. Immunity. 2013; 39(3):443-53. DOI: 10.1016/j.immuni.2013.06.018. View

15.

Chopin M, Seillet C, Chevrier S, Wu L, Wang H, Morse 3rd H . Langerhans cells are generated by two distinct PU.1-dependent transcriptional networks. J Exp Med. 2013; 210(13):2967-80. PMC: 3865480. DOI: 10.1084/jem.20130930. View

16.

Uhlen M, Fagerberg L, Hallstrom B, Lindskog C, Oksvold P, Mardinoglu A . Proteomics. Tissue-based map of the human proteome. Science. 2015; 347(6220):1260419. DOI: 10.1126/science.1260419. View

17.

Blackwell K, Zhang L, Workman L, Ting A, Iwai K, Habelhah H . Two coordinated mechanisms underlie tumor necrosis factor alpha-induced immediate and delayed IκB kinase activation. Mol Cell Biol. 2013; 33(10):1901-15. PMC: 3647962. DOI: 10.1128/MCB.01416-12. View

18.

Vince J, Wong W, Khan N, Feltham R, Chau D, Ahmed A . IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis. Cell. 2007; 131(4):682-93. DOI: 10.1016/j.cell.2007.10.037. View

19.

Hait N, Allegood J, Maceyka M, Strub G, Harikumar K, Singh S . Regulation of histone acetylation in the nucleus by sphingosine-1-phosphate. Science. 2009; 325(5945):1254-7. PMC: 2850596. DOI: 10.1126/science.1176709. View

20.

Sun L, Wang H, Wang Z, He S, Chen S, Liao D . Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell. 2012; 148(1-2):213-27. DOI: 10.1016/j.cell.2011.11.031. View