title: The Tumor Suppressor Hace1 Is a Critical Regulator of TNFR1-Mediated Cell Fate.
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.
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), 1030 Vienna, Austria.
authors.forename: Luigi
authors.initials: L
authors.lastname: Tortola
authors.affiliation: 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.
authors.forename: Roberto
authors.initials: R
authors.lastname: Nitsch
authors.affiliation: Inflammation Research Center, VIB, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Gent University, Technologiepark 927, Zwijnaarde 9052, Belgium.
authors.forename: Mathieu J M
authors.initials: MJM
authors.lastname: Bertrand
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), 1030 Vienna, Austria.
authors.forename: Melanie
authors.initials: M
authors.lastname: Kogler
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), 1030 Vienna, Austria.
authors.forename: Younes
authors.initials: Y
authors.lastname: Redouane
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), 1030 Vienna, Austria.
authors.forename: Ivona
authors.initials: I
authors.lastname: Kozieradzki
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), 1030 Vienna, Austria.
authors.forename: Iris
authors.initials: I
authors.lastname: Uribesalgo
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), 1030 Vienna, Austria.
authors.forename: Lilian M
authors.initials: LM
authors.lastname: Fennell
authors.affiliation: Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, BC V5Z 1M9, Canada.
authors.forename: Mads
authors.initials: M
authors.lastname: Daugaard
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Department of Epigenetics, Stübeweg 51, 79108 Freiburg, Germany.
authors.forename: Helene
authors.initials: H
authors.lastname: Klug
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), 1030 Vienna, Austria.
authors.forename: Gerald
authors.initials: G
authors.lastname: Wirnsberger
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), 1030 Vienna, Austria.
authors.forename: Reiner
authors.initials: R
authors.lastname: Wimmer
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), 1030 Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Perlot
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), 1030 Vienna, Austria.
authors.forename: Renu
authors.initials: R
authors.lastname: Sarao
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), 1030 Vienna, Austria.
authors.forename: Shuan
authors.initials: S
authors.lastname: Rao
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), 1030 Vienna, Austria.
authors.forename: Toshikatsu
authors.initials: T
authors.lastname: Hanada
authors.affiliation: Inflammation Research Center, VIB, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Gent University, Technologiepark 927, Zwijnaarde 9052, Belgium.
authors.forename: Nozomi
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Max F. Perutz Laboratories, University of Vienna, Dr Bohrgasse 9/4, 1030 Vienna, Austria.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kernbauer
authors.affiliation: Max F. Perutz Laboratories, University of Vienna, Dr Bohrgasse 9/4, 1030 Vienna, Austria.
authors.forename: Duygu
authors.initials: D
authors.lastname: Demiröz
authors.affiliation: Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Michaela
authors.initials: M
authors.lastname: Lang
authors.affiliation: CEMM, Centre for Molecular Medicine, 1060 Vienna, Austria.
authors.forename: Giulio
authors.initials: G
authors.lastname: Superti-Furga
authors.affiliation: Max F. Perutz Laboratories, University of Vienna, Dr Bohrgasse 9/4, 1030 Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Decker
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Department of Epigenetics, Stübeweg 51, 79108 Freiburg, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pichler
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), 1030 Vienna, Austria.
authors.forename: Fumiyo
authors.initials: F
authors.lastname: Ikeda
authors.affiliation: 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.
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.affiliation: Inflammation Research Center, VIB, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Gent University, Technologiepark 927, Zwijnaarde 9052, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenabeele
authors.affiliation: Department of Molecular Oncology, BC Cancer Research Center, University of British Columbia, Vancouver, BC V5Z1L3, Canada.
authors.forename: Poul H
authors.initials: PH
authors.lastname: Sorensen
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), 1030 Vienna, Austria. Electronic address: josef.penninger@imba.oeaw.ac.at.
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053181:Caspase 8 / Q000378:metabolism; D019070:Cell Lineage / Q000187:drug effects; D003092:Colitis / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D016264:Dextran Sulfate; D004622:Embryo, Mammalian / Q000166:cytology; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D017353:Gene Deletion; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; D047992:TNF Receptor-Associated Factor 2; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D016264:Dextran Sulfate; C000591483:HACE1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; D053181:Caspase 8