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; Michaela Lang; Giulio Superti-Furga; Thomas Decker; Andrea Pichler; Fumiyo Ikeda; Guido Kroemer; Peter Vandenabeele; Poul H Sorensen; Josef M Penninger

doi:10.1016/j.celrep.2016.04.032

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

Cell Rep. 2016 May 17;15(7):1481-1492. doi: 10.1016/j.celrep.2016.04.032. Epub 2016 May 5.

Authors

Luigi Tortola¹, Roberto Nitsch², Mathieu J M Bertrand³, Melanie Kogler¹, Younes Redouane¹, Ivona Kozieradzki¹, Iris Uribesalgo¹, Lilian M Fennell¹, Mads Daugaard⁴, Helene Klug⁵, Gerald Wirnsberger¹, Reiner Wimmer¹, Thomas Perlot¹, Renu Sarao¹, Shuan Rao¹, Toshikatsu Hanada¹, Nozomi Takahashi³, Elisabeth Kernbauer⁶, Duygu Demiröz⁶, Michaela Lang⁷, Giulio Superti-Furga⁸, Thomas Decker⁶, Andrea Pichler⁵, Fumiyo Ikeda¹, Guido Kroemer⁹, Peter Vandenabeele³, Poul H Sorensen¹⁰, Josef M Penninger¹¹

Affiliations

¹ Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), 1030 Vienna, Austria.
² Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), 1030 Vienna, Austria; Discovery Sciences, IMED Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal 431 83, Sweden.
³ Inflammation Research Center, VIB, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Gent University, Technologiepark 927, Zwijnaarde 9052, Belgium.
⁴ Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, BC V5Z 1M9, Canada.
⁵ Max Planck Institute of Immunobiology and Epigenetics, Department of Epigenetics, Stübeweg 51, 79108 Freiburg, Germany.
⁶ Max F. Perutz Laboratories, University of Vienna, Dr Bohrgasse 9/4, 1030 Vienna, Austria.
⁷ Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, 1090 Vienna, Austria.
⁸ CEMM, Centre for Molecular Medicine, 1060 Vienna, Austria.
⁹ INSERM U848, 39 rue Camille Desmoulins, 94805 Villejuif, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France; Centre de Recherche des Cordeliers, 15 rue de l'Ecole de Médecine, 75006 Paris, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, 75015 Paris, France; Université Paris Descartes/Paris 5, Sorbonne Paris Cité, 75006 Paris, France.
¹⁰ Department of Molecular Oncology, BC Cancer Research Center, University of British Columbia, Vancouver, BC V5Z1L3, Canada.
¹¹ Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), 1030 Vienna, Austria. Electronic address: [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / drug effects
Caspase 8 / metabolism
Cell Lineage* / drug effects
Colitis / metabolism
Colitis / pathology
Colonic Neoplasms / metabolism
Colonic Neoplasms / pathology
Dextran Sulfate
Embryo, Mammalian / cytology
Enzyme Activation / drug effects
Fibroblasts / drug effects
Fibroblasts / metabolism
Gene Deletion
Mice, Inbred C57BL
Mutation / genetics
NF-kappa B / metabolism
Necrosis
Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
Receptors, Tumor Necrosis Factor, Type I / metabolism*
TNF Receptor-Associated Factor 2 / metabolism
Tumor Necrosis Factor-alpha / pharmacology
Tumor Suppressor Proteins / metabolism*
Ubiquitin-Protein Ligases / metabolism*
Ubiquitination / drug effects

Substances

NF-kappa B
Receptors, Tumor Necrosis Factor, Type I
TNF Receptor-Associated Factor 2
Tnfrsf1a protein, mouse
Tumor Necrosis Factor-alpha
Tumor Suppressor Proteins
Dextran Sulfate
HACE1 protein, mouse
Ubiquitin-Protein Ligases
Receptor-Interacting Protein Serine-Threonine Kinases
Ripk3 protein, mouse
Caspase 8