Advertisement

New Perspectives in TNF-R1-Induced NF-κB Signaling

  • Ian E. Gentle
  • John Silke
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 691)

Abstract

The ubiquitylation events leading to activation of NF-κB at the TNFR1 receptor have been a topic of intense study. It is believed that K63 ubiquitylation of the kinase RIPK1 is required for recruitment of the TAB2/TAB3/TAK1 and IKK1/IKK2/NEMO complexes that are in turn required to phosphorylate and degrade IκBα allowing freed NF-κB dimers to nuclear translocation. The exact involvement of the E3 ligases, TRAF2, TRAF5, cIAP1, and cIAP2 in this process has been unclear. We summarize a recent study from our lab defining the roles of TRAF2 and cIAP1 s in activation of NF-κB downstream of TNF-R1 and report the surprising finding that RIPK1 is not essential for TNF-R1-induced NF-κB. Alternative mechanisms of how NF-κB may be activated by TNF-R1 in the light of these findings are discussed.

Keywords

Ring Domain Ubiquitin Chain Death Domain Interaction Linear Ubiquitin Chain Kinase RIPK1 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

We would like to thank Hiroyasu Nakano for TRAF2/TRAF5 double knock-out MEFs, Robert Brink for TRAF2 conditional knock-out mice, Michelle Kelliher for RIPK1 / mice, and James Vince and Lynn Wong for their work that contributed significantly to this chapter.

References

  1. 1.
    Bertrand MJM, Milutinovic S, Dickson KM et al (2008) cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination. Mol Cell 30:689–700CrossRefPubMedGoogle Scholar
  2. 2.
    Doi TS, Marino MW, Takahashi T et al (1999) Absence of tumor necrosis factor rescues RelA-deficient mice from embryonic lethality. Proc Natl Acad Sci USA 96:2994–2999CrossRefPubMedGoogle Scholar
  3. 3.
    Haas TL, Emmerich CH, Gerlach B, Schmukle AC, Cordier SM, Rieser E, Feltham R, Vince J, Warnken U, Wenger T et al (2009) Recruitment of the linear ubiquitin chain assembly complex stabilizes the TNF-R1 signaling complex and is required for TNF-mediated gene induction. Mol Cell 36:831–844Google Scholar
  4. 4.
    Hsu H, Huang J, Shu HB et al (1996) TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex. Immunity 4:387–396CrossRefPubMedGoogle Scholar
  5. 5.
    Kelliher MA, Grimm S, Ishida Y, Kuo F, Stanger BZ, Leder P (1998) The death domain kinase RIP mediates the TNF-induced NF-kappaB signal. Immunity 8:297–303CrossRefPubMedGoogle Scholar
  6. 6.
    Laplantine E, Fontan E, Chiaravalli J et al (2009) NEMO specifically recognizes K63-linked poly-ubiquitin chains through a new bipartite ubiquitin-binding domain. EMBO J 28:2885–2895CrossRefPubMedGoogle Scholar
  7. 7.
    Lee SY, Reichlin A, Santana A et al (1997) TRAF2 is essential for JNK but not NF-kappaB activation and regulates lymphocyte proliferation and survival. Immunity 7:703–713CrossRefPubMedGoogle Scholar
  8. 8.
    Lee T, Shank J, Cusson N et al (2004) The kinase activity of Rip 1 is not required for TNF-alpha-induced Ikk or p38 MAP kinase activation or for the ubiquitination of Rip1 by Traf2. J Biol Chem 279:33185–33191CrossRefPubMedGoogle Scholar
  9. 9.
    Li S, Wang L, Dorf ME (2009) PKC phosphorylation of TRAF2 mediates IKKalpha/beta recruitment and K63-linked polyubiquitination. Mol Cell 33:30–42CrossRefPubMedGoogle Scholar
  10. 10.
    Mahoney DJ, Cheung HH, Mrad RL et al (2008) Both cIAP1 and cIAP2 regulate TNFalpha-mediated NF-kappaB activation. Proc Natl Acad Sci USA 105:11778–11783CrossRefPubMedGoogle Scholar
  11. 11.
    Nakano H, Sakon S, Koseki H et al (1999) Targeted disruption of Traf5 gene causes defects in CD40- and CD27-mediated lymphocyte activation. Proc Natl Acad Sci U S A 96:9803–9808CrossRefPubMedGoogle Scholar
  12. 12.
    Ndubaku C, Varfolomeev E, Wang L et al (2009) Antagonism of c-IAP and XIAP proteins is required for efficient induction of cell death by small-molecule IAP antagonists. ACS Chem Biol 4:557–566CrossRefPubMedGoogle Scholar
  13. 13.
    Okazaki T, Sakon S, Sasazuki T et al (2003) Phosphorylation of serine 276 is essential for p65 NF-κB subunit-dependent cellular responses. Biochem Biophy Res Commun 300:807–812CrossRefGoogle Scholar
  14. 14.
    Park YC, Ye H, Hsia C et al (2000) A novel mechanism of TRAF signaling revealed by structural and functional analyses of the TRADD-TRAF2 interaction. Cell 101:777–787CrossRefPubMedGoogle Scholar
  15. 15.
    Rothe M, Pan MG, Henzel WJ et al (1995) The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins. Cell 83:1243–1252CrossRefPubMedGoogle Scholar
  16. 16.
    Sanjo H, Takeda K, Tsujimura T et al (2003) TAB2 is essential for prevention of apoptosis in fetal liver but not for interleukin-1 signaling. Mol Cell Biol 23:1231–1238CrossRefPubMedGoogle Scholar
  17. 17.
    Schmidt-Supprian M, Bloch W, Courtois G et al (2000) NEMO/IKK gamma-deficient mice model incontinentia pigmenti. Mol Cell 5:981–992CrossRefPubMedGoogle Scholar
  18. 18.
    Tada K, Okazaki T, Sakon S et al (2001) Critical roles of TRAF2 and TRAF5 in tumor necrosis factor-induced NF-kappa B activation and protection from cell death. J Biol Chem 276:36530–36534CrossRefPubMedGoogle Scholar
  19. 19.
    Tokunaga F, Sakata S-I, Saeki Y et al (2009) Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation. Nat Cell Biol 11:123–132CrossRefPubMedGoogle Scholar
  20. 20.
    Tsao DH, McDonagh T, Telliez JB et al (2000) Solution structure of N-TRADD and characterization of the interaction of N-TRADD and C-TRAF2, a key step in the TNFR1 signaling pathway. Mol Cell 5:1051–1057CrossRefPubMedGoogle Scholar
  21. 21.
    Uren AG, Pakusch M, Hawkins CJ et al (1996) Cloning and expression of apoptosis inhibitory protein homologs that function to inhibit apoptosis and/or bind tumor necrosis factor receptor-associated factors. Proc Natl Acad Sci USA 93:4974–4978CrossRefPubMedGoogle Scholar
  22. 22.
    Varfolomeev E, Goncharov T, Fedorova AV et al (2008) c-IAP1 and c-IAP2 are critical mediators of tumor necrosis factor (TNF) induced NF-κB activation. J Biol Chem 283:24295–24299CrossRefPubMedGoogle Scholar
  23. 23.
    Vince JE, Chau D, Callus B et al (2008) TWEAK-FN14 signaling induces lysosomal degradation of a cIAP1-TRAF2 complex to sensitize tumor cells to TNF. J Cell Biol 182:171–184CrossRefPubMedGoogle Scholar
  24. 24.
    Vince JE, Pantaki D, Feltham R, Mace PD, Cordier SM, Schmukle AC, Davidson AJ, Callus BA, Wong WW, Gentle IE et al (2009) TRAF2 must bind to cellular inhibitors of apoptosis for tumor necrosis factor (TNF) to efficiently activate NF-κB and to prevent tnf-induced apoptosis. J Biol Chem 284:35906–35915Google Scholar
  25. 25.
    Vince JE, Wong WWL, Khan N et al (2007) IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis. Cell 131:682–693CrossRefPubMedGoogle Scholar
  26. 26.
    Wang C, Deng L, Hong M et al (2001) TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 412:346–351CrossRefPubMedGoogle Scholar
  27. 27.
    Wang L, Du F, Wang X (2008) TNF-alpha induces two distinct caspase-8 activation pathways. Cell 133:693–703CrossRefPubMedGoogle Scholar
  28. 28.
    Wertz IE, O’Rourke KM, Zhou H et al (2004) De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature 430:694–699CrossRefPubMedGoogle Scholar
  29. 29.
    Wong WW, Gentle I, Carter H et al (2009) RIPK1 is not essential for TNFR1 induced activation of NF-κB. Cell Death Differ (in press)Google Scholar
  30. 30.
    Wu CJ, Conze DB, Li T et al (2006) NEMO is a sensor of Lys 63-linked polyubiquitination and functions in NF-κB activation. Nat Cell Biol 8:398–406CrossRefPubMedGoogle Scholar
  31. 31.
    Xia ZP, Sun L, Chen X, Pineda G, Jiang X, Adhikari A, Zeng W, Chen ZJ (2009) Direct activation of protein kinases by unanchored polyubiquitin chains. Nature 461:114–119CrossRefPubMedGoogle Scholar
  32. 32.
    Yamamoto M, Okamoto T, Takeda K et al (2006) Key function for the Ubc13 E2 ubiquitin-conjugating enzyme in immune receptor signaling. Nat Immunol 7:962–970CrossRefPubMedGoogle Scholar
  33. 33.
    Yeh WC, Shahinian A, Speiser D et al (1997) Early lethality, functional NF-kappaB activation, and increased sensitivity to TNF-induced cell death in TRAF2-deficient mice. Immunity 7:715–725CrossRefPubMedGoogle Scholar
  34. 34.
    Yin Q, Lamothe B, Darnay BG et al (2009) Structural basis for lack of E2 interaction in the RING of TRAF2. Biochemistry 091007182844046Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of BiochemistryLa Trobe UniversityMelbourneAustralia

Personalised recommendations