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

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. M...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4893156/
https://www.ncbi.nlm.nih.gov/pubmed/27160902
http://dx.doi.org/10.1016/j.celrep.2016.04.032
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author 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.
author_facet 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.
author_sort Tortola, Luigi
collection PubMed
description 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.
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spelling pubmed-48931562016-06-13 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. Cell Rep Article 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. Cell Press 2016-05-05 /pmc/articles/PMC4893156/ /pubmed/27160902 http://dx.doi.org/10.1016/j.celrep.2016.04.032 Text en © 2016 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
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
title The Tumor Suppressor Hace1 Is a Critical Regulator of TNFR1-Mediated Cell Fate
title_full The Tumor Suppressor Hace1 Is a Critical Regulator of TNFR1-Mediated Cell Fate
title_fullStr The Tumor Suppressor Hace1 Is a Critical Regulator of TNFR1-Mediated Cell Fate
title_full_unstemmed The Tumor Suppressor Hace1 Is a Critical Regulator of TNFR1-Mediated Cell Fate
title_short The Tumor Suppressor Hace1 Is a Critical Regulator of TNFR1-Mediated Cell Fate
title_sort tumor suppressor hace1 is a critical regulator of tnfr1-mediated cell fate
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4893156/
https://www.ncbi.nlm.nih.gov/pubmed/27160902
http://dx.doi.org/10.1016/j.celrep.2016.04.032
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