TY - JOUR
T1 - The Tumor Suppressor Hace1 Is a Critical Regulator of TNFR1-Mediated Cell Fate
AU - Tortola, Luigi
AU - Nitsch, Roberto
AU - Bertrand, Mathieu J.M.
AU - Kogler, Melanie
AU - Redouane, Younes
AU - Kozieradzki, Ivona
AU - Uribesalgo, Iris
AU - Fennell, Lilian M.
AU - Daugaard, Mads
AU - Klug, Helene
AU - Wirnsberger, Gerald
AU - Wimmer, Reiner
AU - Perlot, Thomas
AU - Sarao, Renu
AU - Rao, Shuan
AU - Hanada, Toshikatsu
AU - Takahashi, Nozomi
AU - Kernbauer, Elisabeth
AU - Demiröz, Duygu
AU - Superti-Furga, Giulio
AU - Decker, Thomas
AU - Pichler, Andrea
AU - Ikeda, Fumiyo
AU - Kroemer, Guido
AU - Vandenabeele, Peter
AU - Sorensen, Poul H.
AU - Penninger, Josef M.
N1 - Funding Information:
We thank all members of our laboratories and Helen Pickersgill for critical reading and expert advice, and we thank Cecile Pickart and Marc Timmers for the bacterial ubiquitin E2-expressing plasmids. We are grateful to the members of the IMP-IMBA Biooptics facility for assistance in cell sorting. SMAC mimetic BV6 and RIP3 kinase mutant mice were generously obtained by Genentech. The work was supported by the Austrian Academy of Sciences and an advanced European Research Council (ERC) grant (to J.M.P.), the Helmsley Foundation (VEO-IBD, to J.M.P.), an Innovator award by Era of Hope (to J.M.P.), the Max Planck Society (to A.P.), WWTF LS05003 (to A.P.), DFG PI 917/1-1 (to A.P.), and by the Swiss National Science Foundation (PBEZP3_145993 to L.T.). M.J.M.B. has a tenure track position in the Multidisciplinary Research Program of Ghent University (GROUP-ID). G.K. is supported by the Ligue Nationale contre le Cancer, Agence Nationale pour la Recherche, European Commission (ArtForce), Institut National du Cancer (INCa), Cancéropôle Ile-de-France, Fondation Bettencourt-Schueller, LabEx Immuno-Oncology, and PACRI. P.V. is supported by European grants (FP7 EC RTD Integrated Project, Apo-Sys, FP7-200767; Euregional PACT II), Belgian grants (Interuniversity Attraction Poles, IAP 6/18), Flemish grants (Research Foundation Flanders, FWO G.0875.11 and FWO G.0973.11), Ghent University grants (MRP, GROUP-ID consortium), and grants from Flanders Institute for Biotechnology (VIB). P.V. also holds a Methusalem grant (BOF09/01M00709) from the Flemish Government. R.N. is currently an employee of AstraZeneca; however, he contributed to this study during his previous occupation at IMBA.
Publisher Copyright:
© 2016 The Authors.
PY - 2016/5/17
Y1 - 2016/5/17
N2 - 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. Tortola et al. report that the E3 ubiquitin ligase HACE1 is a gatekeeper of TNFR1-mediated cell fate. Hace1 deficiency impairs TNF-driven NF-κB activation and apoptosis and predisposes cells to necroptosis. Consequently, hace1-/- mice show enhanced colitis and colon cancer, which can be reverted by inactivation of pro-necroptotic kinase RIP3 and TNFR1.
AB - 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. Tortola et al. report that the E3 ubiquitin ligase HACE1 is a gatekeeper of TNFR1-mediated cell fate. Hace1 deficiency impairs TNF-driven NF-κB activation and apoptosis and predisposes cells to necroptosis. Consequently, hace1-/- mice show enhanced colitis and colon cancer, which can be reverted by inactivation of pro-necroptotic kinase RIP3 and TNFR1.
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U2 - 10.1016/j.celrep.2016.04.032
DO - 10.1016/j.celrep.2016.04.032
M3 - Article
C2 - 27160902
AN - SCOPUS:84964956247
SN - 2211-1247
VL - 15
SP - 1481
EP - 1492
JO - Cell Reports
JF - Cell Reports
IS - 7
ER -
