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

Luigi Tortola | Zendy; Roberto Nitsch | Zendy; Mathieu J.M. Bertrand | Zendy; Melanie Kögler | Zendy; Younes Redouane | Zendy; I. Kozieradzki | Zendy; Iris Uribesalgo | Zendy; Lilian M. Fennell | Zendy; Mads Daugaard | Zendy; Helene Klug | Zendy; Gerald Wirnsberger | Zendy; Reiner Wimmer | Zendy; Thomas Perlot | Zendy; Renu Sarao | Zendy; Shuan Rao | Zendy; Toshikatsu Hanada | Zendy; Nozomi Takahashi | Zendy; Elisabeth Kernbauer | Zendy; Duygu Demiröz | Zendy; Michaela Lang | Zendy; Giulio SupertiFurga | Zendy; Thomas Decker | Zendy; Andrea Pichler | Zendy; Fumiyo Ikeda | Zendy; Guido Kroemer | Zendy; Peter Vandenabeele | Zendy; Poul H. Sorensen | Zendy; Josef Penninger | Zendy

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

Author(s) -

Luigi Tortola,

Roberto Nitsch,

Mathieu J.M. Bertrand,

Melanie Kögler,

Younes Redouane,

I. 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 SupertiFurga,

Thomas Decker,

Andrea Pichler,

Fumiyo Ikeda,

Guido Kroemer,

Peter Vandenabeele,

Poul H. Sorensen,

Josef Penninger

Publication year - 2016

Publication title -

cell reports

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 6.264

H-Index - 154

eISSN - 2639-1856

pISSN - 2211-1247

DOI - 10.1016/j.celrep.2016.04.032

Subject(s) - regulator , cell fate determination , suppressor , microbiology and biotechnology , chemistry , master regulator , cell , biology , biochemistry , transcription factor , gene

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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