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Activation of the NF-κB pathway by Caspase 8 and its homologs

Oncogene volume 19, pages 4451–4460 (2000)Cite this article

Abstract

Caspase 8 is the most proximal caspase in the caspase cascade and has been known for its role in the mediation of cell death by various death receptors belonging to the TNFR family. We have discovered that Caspase 8 can activate the NF-κB pathway independent of its activity as a pro-apoptotic protease. This property is localized to its N-terminal prodomain, which contains two homologous death effector domains (DEDs). Caspase 10 and MRIT, two DEDs-containing homologs of Caspase 8, can similarly activate the NF-κB pathway. Dominant-negative mutants of the Caspase 8 prodomain can block NF-κB induced by Caspase 8, FADD and several death receptors belonging to the TNFR family. Caspase 8 can interact with multiple proteins known to be involved in the activation of the NF-κB pathway, including the serine-threonine kinases RIP, NIK, IKK1 and IKK2. Thus, DEDs-containing caspases and caspase homolog(s) may have functions beyond their known role in the mediation of cell death.

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References

  • Ashkenazi A and Dixit VM. . 1998 Science 281: 1305–1308.

  • Baker SJ and Reddy EP. . 1996 Oncogene 12: 1–9.

  • Berberich I, Shu GL and Clark EA. . 1994 J. Immunol. 153: 4357–4366.

  • Boldin MP, Goncharov TM, Goltsev YV and Wallach D. . 1996 Cell 85: 803–815.

  • Boldin MP, Varfolomeev EE, Pancer Z, Mett IL, Camonis JH and Wallach D. . 1995 J. Biol. Chem. 270: 7795–7798.

  • Brockman JA, Scherer DC, McKinsey TA, Hall SM, Qi X, Lee WY and Ballard DW. . 1995 Mol. Cell. Biol. 15: 2809–2818.

  • Chaudhary PM, Eby M, Jasmin A, Bookwalter A, Murray J and Hood L. . 1997 Immunity. 7: 821–830.

  • Chaudhary PM, Eby MT, Jasmin A and Hood L. . 1999 J. Biol. Chem. 274: 19211–19219.

  • Chinnaiyan AM and Dixit VM. . 1997 Semin. Immunol. 9: 69–76.

  • Chinnaiyan AM, O'Rourke K, Tewari M and Dixit VM. . 1995 Cell 81: 505–512.

  • Chinnaiyan AM, Tepper CG, Seldin MF, O'Rourke K, Kischkel FC, Hellbardt S, Krammer PH, Peter ME and Dixit VM. . 1996 J. Biol. Chem. 271: 4961–4965.

  • DiDonato JA, Hayakawa M, Rothwarf DM, Zandi E and Karin M. . 1997 Nature 388: 548–554.

  • Fernandes-Alnernri T, Armstrong RC, Krebs J, Srinivasula SM, Wang L, Bullrich F, Fritz LC, Trapani JA, Tomaselli KJ, Litwack G and Alnemri ES. . 1996 Proc. Natl. Acad. Sci. USA 93: 7464–7469.

  • Goltsev YV, Kovalenko AV, Arnold E, Varfolomeev EE, Brodianskii VM and Wallach D. . 1997 J. Biol. Chem. 272: 19641–19644.

  • Grimm S, Bauer MK, Baeuerle PA and Schulze-Osthoff K. . 1996 J. Cell. Biol. 134: 13–23.

  • Han DK, Chaudhary PM, Wright ME, Friedman C, Trask BJ, Riedel RT, Baskin DG, Schwartz SM and Hood L. . 1997 Proc. Natl. Acad. Sci. USA 94: 11333–11338.

  • Hettmann T, DiDonato J, Karin M and Leiden JM. . 1999 J. Exp. Med. 189: 145–158.

  • Hsu H, Shu HB, Pan MG and Goeddel DV. . 1996 Cell 84: 299–308.

  • Hsu H, Solovyev I, Colombero A, Elliott R, Kelley M and Boyle WJ. . 1997 J. Biol. Chem. 272: 13471–13474.

  • Hsu H, Xiong J and Goeddel DV. . 1995 Cell 81: 495–504.

  • Hu S, Vincenz C, Ni J, Gentz R and Dixit VM. . 1997 J. Biol. Chem. 272: 17255–17257.

  • Inohara N, Koseki T, Hu Y, Chen S and Nunez G. . 1997 Proc. Natl. Acad. Sci. USA 94: 10717–10722.

  • Irmler M, Thome M, Hahne M, Schneider P, Hofmann K, Steiner V, Bodmer JL, Schroter M, Burns K, Mattmann C, Rimoldi D, French LE and Tschopp J. . 1997 Nature 388: 190–195.

  • Jung M, Zhang Y, Lee S and Dritschilo A. . 1995 Science 268: 1619–1621.

  • Kelliher MA, Grimm S, Ishida Y, Kuo F, Stanger BZ and Leder P. . 1998 Immunity 8: 297–303.

  • Lin KI, DiDonato JA, Hoffmann A, Hardwick JM and Ratan RR. . 1998 J. Cell. Biol. 141: 1479–1487.

  • Liu ZG, Hsu H, Goeddel DV and Karin M. . 1996 Cell 87: 565–576.

  • Malinin NL, Boldin MP, Kovalenko AV and Wallach D. . 1997 Nature 385: 540–544.

  • Mercurio F, Zhu H, Murray BW, Shevchenko A, Bennett BL, Li J, Young DB, Barbosa M, Mann M, Manning A and Rao A. . 1997 Science 278: 860–866.

  • Muzio M, Chinnaiyan AM, Kischkel FC, O'Rourke K, Shevchenko A, Ni J, Scaffidi C, Bretz JD, Zhang M, Gentz R, Mann M, Krammer PH, Peter ME and Dixit VM. . 1996 Cell 85: 817–827.

  • Nakano H, Shindo M, Sakon S, Nishinaka S, Mihara M, Yagita H and Okumura K. . 1998 Proc. Natl. Acad. Sci. USA 95: 3537–3542.

  • Natoli G, Costanzo A, Moretti F, Fulco M, Balsano C and Levrero M. . 1997 J. Biol. Chem. 272: 26079–26082.

  • Regnier CH, Song HY, Gao X, Goeddel DV, Cao Z and Rothe M. . 1997 Cell 90: 373–383.

  • Shu HB, Halpin DR and Goeddel DV. . 1997 Immunity 6: 751–763.

  • Srinivasula SM, Ahmad M, Ottilie S, Bullrich F, Banks S, Wang Y, Fernandes-Alnemri T, Croce CM, Litwack G, Tomaselli KJ, Armstrong RC and Alnemri ES. . 1997 J. Biol. Chem. 272: 18542–18545.

  • Takeuchi M, Rothe M and Goeddel DV. . 1996 J. Biol. Chem. 271: 19935–19942.

  • Varfolomeev EE, Boldin MP, Goncharov TM and Wallach D. . 1996 J. Exp. Med. 183: 1271–1275.

  • Varfolomeev EE, Schuchmann M, Luria V, Chiannilkulchai N, Beckmann JS, Mett IL, Rebrikov D, Brodianski VM, Kemper OC, Kollet O, Lapidot T, Soffer D, Sobe T, Avraham KB, Goncharov T, Holtmann H, Lonai P and Wallach D. . 1998 Immunity 9: 267–276.

  • Vincenz C and Dixit VM. . 1997 J. Biol. Chem. 272: 6578–6583.

  • Wang CY, Mayo MW, Korneluk RG, Goeddel DV and Baldwin Jr AS. . 1998 Science 281: 1680–1683.

  • Woronicz JD, Gao X, Cao Z, Rothe M and Goeddel DV. . 1997 Science 278: 866–869.

  • Wu MX, Ao Z, Prasad KV, Wu R and Schlossman SF. . 1998 Science 281: 998–1001.

  • Yeh WC, Pompa JL, McCurrach ME, Shu HB, Elia AJ, Shahinian A, Ng M, Wakeham A, Khoo W, Mitchell K, El-Deiry WS, Lowe SW, Goeddel DV and Mak TW. . 1998 Science 279: 1954–1958.

  • Yeh WC, Shahinian A, Speiser D, Kraunus J, Billia F, Wakeham A, de la Pompa JL, Ferrick D, Hum B, Iscove N, Ohashi P, Rothe M, Goeddel DV and Mak TW. . 1997 Immunity 7: 715–725.

  • Zandi E, Rothwarf DM, Delhase M, Hayakawa M and Karin M. . 1997 Cell 91: 243–252.

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Acknowledgements

We would like to thank Drs Emad Alnemri, Vishva Dixit, David Han and Michael Wright for the CrmA, FADD and various caspase expression plasmids, Dr Edward Clark for the NF-κB reporter plasmid, Dr Hiroyasu Nakano for IKKs expression plasmids and Dr Gioacchino Natoli for NIK expression plasmids. PMC was supported by a postdoctoral fellowship from the Cancer Research Fund of the Damon Runyon-Walter Winchell Foundation.

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Authors and Affiliations

  1. Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, 75390-8593, Texas, TX, USA

    Preet M Chaudhary, Michael T Eby, Alan Jasmin, Arvind Kumar & Li Liu

  2. Department of Molecular Biotechnology, University of Washington, Seattle, 98195, Washington, WA, USA

    Leroy Hood

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  1. Preet M Chaudhary
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  2. Michael T Eby
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Chaudhary, P., Eby, M., Jasmin, A. et al. Activation of the NF-κB pathway by Caspase 8 and its homologs. Oncogene 19, 4451–4460 (2000). https://doi.org/10.1038/sj.onc.1203812

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