The Tumor Suppressor Hace1 Is a Critical Regulator of TNFR1-Mediated Cell Fate

Luigi Tortola, Roberto Nitsch, Mathieu J.M. Bertrand, Melanie Kogler, Younes Redouane, Ivona Kozieradzki, Iris Uribesalgo, Lilian M. Fennell, Mads Daugaard, Helene Klug, Gerald Wirnsberger, Reiner Wimmer, Thomas Perlot, Renu Sarao, Shuan Rao, Toshikatsu Hanada, Nozomi Takahashi, Elisabeth Kernbauer, Duygu Demiröz, Giulio Superti-FurgaThomas Decker, Andrea Pichler, Fumiyo Ikeda, Guido Kroemer, Peter Vandenabeele, Poul H. Sorensen, Josef M. Penninger

Research output: Contribution to journalArticle

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Abstract

The HECT domain E3 ligase HACE1 has been identified as a tumor suppressor in multiple cancers. Here, we report that HACE1 is a central gatekeeper of TNFR1-induced cell fate. Genetic inactivation of HACE1 inhibits TNF-stimulated NF-κB activation and TNFR1-NF-κB-dependent pathogen clearance in vivo. Moreover, TNF-induced apoptosis was impaired in hace1 mutant cells and knockout mice in vivo. Mechanistically, HACE1 is essential for the ubiquitylation of the adaptor protein TRAF2 and formation of the apoptotic caspase-8 effector complex. Intriguingly, loss of HACE1 does not impair TNFR1-mediated necroptotic cell fate via RIP1 and RIP3 kinases. Loss of HACE1 predisposes animals to colonic inflammation and carcinogenesis in vivo, which is markedly alleviated by genetic inactivation of RIP3 kinase and TNFR1. Thus, HACE1 controls TNF-elicited cell fate decisions and exerts tumor suppressor and anti-inflammatory activities via a TNFR1-RIP3 kinase-necroptosis pathway. Tortola et al. report that the E3 ubiquitin ligase HACE1 is a gatekeeper of TNFR1-mediated cell fate. Hace1 deficiency impairs TNF-driven NF-κB activation and apoptosis and predisposes cells to necroptosis. Consequently, hace1-/- mice show enhanced colitis and colon cancer, which can be reverted by inactivation of pro-necroptotic kinase RIP3 and TNFR1.

Original languageEnglish
Pages (from-to)1481-1492
Number of pages12
JournalCell Reports
Volume15
Issue number7
DOIs
Publication statusPublished - May 17 2016

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Receptors, Tumor Necrosis Factor, Type I
Tumors
Phosphotransferases
Neoplasms
Ubiquitin-Protein Ligases
TNF Receptor-Associated Factor 2
Chemical activation
Apoptosis
Caspase 8
Ubiquitination
Pathogens
Colitis
Knockout Mice
Colonic Neoplasms
Carcinogenesis
Animals
Anti-Inflammatory Agents
Inflammation

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Tortola, L., Nitsch, R., Bertrand, M. J. M., Kogler, M., Redouane, Y., Kozieradzki, I., ... Penninger, J. M. (2016). The Tumor Suppressor Hace1 Is a Critical Regulator of TNFR1-Mediated Cell Fate. Cell Reports, 15(7), 1481-1492. https://doi.org/10.1016/j.celrep.2016.04.032

The Tumor Suppressor Hace1 Is a Critical Regulator of TNFR1-Mediated Cell Fate. / Tortola, Luigi; Nitsch, Roberto; Bertrand, Mathieu J.M.; Kogler, Melanie; Redouane, Younes; Kozieradzki, Ivona; Uribesalgo, Iris; Fennell, Lilian M.; Daugaard, Mads; Klug, Helene; Wirnsberger, Gerald; Wimmer, Reiner; Perlot, Thomas; Sarao, Renu; Rao, Shuan; Hanada, Toshikatsu; Takahashi, Nozomi; Kernbauer, Elisabeth; Demiröz, Duygu; Superti-Furga, Giulio; Decker, Thomas; Pichler, Andrea; Ikeda, Fumiyo; Kroemer, Guido; Vandenabeele, Peter; Sorensen, Poul H.; Penninger, Josef M.

In: Cell Reports, Vol. 15, No. 7, 17.05.2016, p. 1481-1492.

Research output: Contribution to journalArticle

Tortola, L, Nitsch, R, Bertrand, MJM, Kogler, M, Redouane, Y, Kozieradzki, I, Uribesalgo, I, Fennell, LM, Daugaard, M, Klug, H, Wirnsberger, G, Wimmer, R, Perlot, T, Sarao, R, Rao, S, Hanada, T, Takahashi, N, Kernbauer, E, Demiröz, D, Superti-Furga, G, Decker, T, Pichler, A, Ikeda, F, Kroemer, G, Vandenabeele, P, Sorensen, PH & Penninger, JM 2016, 'The Tumor Suppressor Hace1 Is a Critical Regulator of TNFR1-Mediated Cell Fate', Cell Reports, vol. 15, no. 7, pp. 1481-1492. https://doi.org/10.1016/j.celrep.2016.04.032
Tortola L, Nitsch R, Bertrand MJM, Kogler M, Redouane Y, Kozieradzki I et al. The Tumor Suppressor Hace1 Is a Critical Regulator of TNFR1-Mediated Cell Fate. Cell Reports. 2016 May 17;15(7):1481-1492. https://doi.org/10.1016/j.celrep.2016.04.032
Tortola, Luigi ; Nitsch, Roberto ; Bertrand, Mathieu J.M. ; Kogler, Melanie ; Redouane, Younes ; Kozieradzki, Ivona ; Uribesalgo, Iris ; Fennell, Lilian M. ; Daugaard, Mads ; Klug, Helene ; Wirnsberger, Gerald ; Wimmer, Reiner ; Perlot, Thomas ; Sarao, Renu ; Rao, Shuan ; Hanada, Toshikatsu ; Takahashi, Nozomi ; Kernbauer, Elisabeth ; Demiröz, Duygu ; Superti-Furga, Giulio ; Decker, Thomas ; Pichler, Andrea ; Ikeda, Fumiyo ; Kroemer, Guido ; Vandenabeele, Peter ; Sorensen, Poul H. ; Penninger, Josef M. / The Tumor Suppressor Hace1 Is a Critical Regulator of TNFR1-Mediated Cell Fate. In: Cell Reports. 2016 ; Vol. 15, No. 7. pp. 1481-1492.
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AU - Tortola, Luigi

AU - Nitsch, Roberto

AU - Bertrand, Mathieu J.M.

AU - Kogler, Melanie

AU - Redouane, Younes

AU - Kozieradzki, Ivona

AU - Uribesalgo, Iris

AU - Fennell, Lilian M.

AU - Daugaard, Mads

AU - Klug, Helene

AU - Wirnsberger, Gerald

AU - Wimmer, Reiner

AU - Perlot, Thomas

AU - Sarao, Renu

AU - Rao, Shuan

AU - Hanada, Toshikatsu

AU - Takahashi, Nozomi

AU - Kernbauer, Elisabeth

AU - Demiröz, Duygu

AU - Superti-Furga, Giulio

AU - Decker, Thomas

AU - Pichler, Andrea

AU - Ikeda, Fumiyo

AU - Kroemer, Guido

AU - Vandenabeele, Peter

AU - Sorensen, Poul H.

AU - Penninger, Josef M.

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N2 - The HECT domain E3 ligase HACE1 has been identified as a tumor suppressor in multiple cancers. Here, we report that HACE1 is a central gatekeeper of TNFR1-induced cell fate. Genetic inactivation of HACE1 inhibits TNF-stimulated NF-κB activation and TNFR1-NF-κB-dependent pathogen clearance in vivo. Moreover, TNF-induced apoptosis was impaired in hace1 mutant cells and knockout mice in vivo. Mechanistically, HACE1 is essential for the ubiquitylation of the adaptor protein TRAF2 and formation of the apoptotic caspase-8 effector complex. Intriguingly, loss of HACE1 does not impair TNFR1-mediated necroptotic cell fate via RIP1 and RIP3 kinases. Loss of HACE1 predisposes animals to colonic inflammation and carcinogenesis in vivo, which is markedly alleviated by genetic inactivation of RIP3 kinase and TNFR1. Thus, HACE1 controls TNF-elicited cell fate decisions and exerts tumor suppressor and anti-inflammatory activities via a TNFR1-RIP3 kinase-necroptosis pathway. Tortola et al. report that the E3 ubiquitin ligase HACE1 is a gatekeeper of TNFR1-mediated cell fate. Hace1 deficiency impairs TNF-driven NF-κB activation and apoptosis and predisposes cells to necroptosis. Consequently, hace1-/- mice show enhanced colitis and colon cancer, which can be reverted by inactivation of pro-necroptotic kinase RIP3 and TNFR1.

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