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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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2016
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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. |
format | Online Article Text |
id | pubmed-4893156 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
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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