The Tumor Suppressor Hace1 Is a Critical Regulator of TNFR1-Mediated Cell Fate
Open accessAbstract
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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Complex II formation also requires TRAF2 ubiquitination by HACE1.
“Complex II formation also requires TRAF2 ubiquitination by HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1) [339].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [339]
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References 73 · Cited by 64
- Authors
- Tortola, L., Nitsch, R., Bertrand, M. J. M., Kogler, M., Redouane, Y., Kozieradzki, I., Uribesalgo, I., Fennell, L. M., Daugaard, M., Klug, H., Wirnsberger, G., Wimmer, R., Perlot, T., Sarao, R., Rao, S., Hanada, T., Takahashi, N., Kernbauer, E., Demiröz, D., Lang, M., Superti-Furga, G., Decker, T., Pichler, A., Ikeda, F., Kroemer, G., Vandenabeele, P., Sorensen, P. H., & Penninger, J. M.
- Affiliations
- Institute of Molecular Biotechnology (AT)
- Ghent University (BE)
- University of British Columbia (CA)
- Max Planck Institute of Immunobiology and Epigenetics (DE)
- University of Vienna (AT)
- Medical University of Vienna (AT)
- Inserm (FR)
- Corresponding author
- Penninger, Josef M.
- ORCID
- Tortola, Luigi
- Nitsch, Roberto
- Bertrand, Mathieu J.M.
- Kozieradzki, Ivona
- Uribesalgo, Iris
- Fennell, Lilian M.
- Daugaard, Mads
- Wirnsberger, Gerald
- Wimmer, Reiner
- Rao, Shuan
- Hanada, Toshikatsu
- Takahashi, Nozomi
- Demiröz, Duygu
- Lang, Michaela
- Decker, Thomas
- Pichler, Andrea
- Ikeda, Fumiyo
- Kroemer, Guido
- Vandenabeele, Peter
- Sorensen, Poul H.
- Penninger, Josef M.
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2016-05
- Volume
- 15
- Issue
- 7
- Pages
- 1481-1492
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC4893156
- OpenAlex
- W2346262847
- Cited by
- 64
- References
- 73
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 4 · 2023: 9 · 2022: 11 · 2021: 7 · 2020: 7 · 2019: 10 · 2018: 8 · 2017: 2 · 2016: 1
- FWCI
- 3.64
- Type
- journal article
- Language
- en
- Update notices
- erratum (2016-09-20)
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion, cc-by)
- Phaidra (Universität Wien) (submittedVersion, cc-by-nc-nd)
- HAL (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (PBEZP3_145993)
- Deutsche Forschungsgemeinschaft (PI 917/1-1)
- European Commission
- Max-Planck-Gesellschaft
- Institut National Du Cancer
- Vlaams Instituut voor Biotechnologie
- Labex Immuno-Oncology
- Ligue Contre le Cancer
- Österreichischen Akademie der Wissenschaften
- European Research Council
- Vienna Science and Technology Fund (LS05003)
- Fonds Wetenschappelijk Onderzoek (FWO G.0875.11)
- Agence Nationale pour le Développement de la Recherche en Santé
- Universiteit Gent
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- HACE1, HECT E3 ubiquitin ligase, tumor suppressor, TNFR1, TNF signaling, NF-κB activation, caspase-8, apoptosis, necroptosis, RIP1 kinase, colitis-associated colorectal cancer, colonic inflammation, anti-inflammatory activity, pathogen clearance
- MeSH terms
- Animals, Colitis, Colonic Neoplasms, Embryo, Mammalian, Enzyme Activation, Fibroblasts, Mice, Inbred C57BL, Mutation, Necrosis, Tumor Necrosis Factor-alpha, Dextran Sulfate, NF-kappa B, Apoptosis, Gene Deletion, Cell Lineage, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Receptors, Tumor Necrosis Factor, Type I, TNF Receptor-Associated Factor 2, Caspase 8, Receptor-Interacting Protein Serine-Threonine Kinases, Ubiquitination
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