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The tumor suppressor Hace1 is a critical regulator of TNFR1-mediated cell fate

(2016) CELL REPORTS. 15(7). p.1481-1492
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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-kappa B activation and TNFR1-NF-kappa B-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.
Keywords
INDUCED APOPTOSIS, UBIQUITIN SYSTEM, ADAPTIVE IMMUNITY, PROGRAMMED NECROSIS, CASPASE-8 ACTIVATION, NF-KAPPA-B, DEXTRAN SODIUM-SULFATE, NECROSIS-FACTOR, TNF-ALPHA, CANCER-THERAPY

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Chicago
Tortola, Luigi, Roberto Nitsch, Mathieu Bertrand, Melanie Kogler, Younes Redouane, Ivona Kozieradzki, Iris Uribesalgo, et al. 2016. “The Tumor Suppressor Hace1 Is a Critical Regulator of TNFR1-mediated Cell Fate.” Cell Reports 15 (7): 1481–1492.
APA
Tortola, L., Nitsch, R., Bertrand, M., Kogler, M., Redouane, Y., Kozieradzki, I., Uribesalgo, I., et al. (2016). The tumor suppressor Hace1 is a critical regulator of TNFR1-mediated cell fate. CELL REPORTS, 15(7), 1481–1492.
Vancouver
1.
Tortola L, Nitsch R, Bertrand M, Kogler M, Redouane Y, Kozieradzki I, et al. The tumor suppressor Hace1 is a critical regulator of TNFR1-mediated cell fate. CELL REPORTS. 2016;15(7):1481–92.
MLA
Tortola, Luigi, Roberto Nitsch, Mathieu Bertrand, et al. “The Tumor Suppressor Hace1 Is a Critical Regulator of TNFR1-mediated Cell Fate.” CELL REPORTS 15.7 (2016): 1481–1492. Print.
@article{7250178,
  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-kappa B activation and TNFR1-NF-kappa B-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.},
  author       = {Tortola, Luigi and Nitsch, Roberto and Bertrand, Mathieu and Kogler, Melanie and Redouane, Younes and Kozieradzki, Ivona and Uribesalgo, Iris and Fennell, Lilian M and Daugaard, Mads and Klug, Helene and Wirnsberger, Gerald and Wimmer, Reiner and Perlot, Thomas and Sarao, Renu and Rao, Shuan and Hanada, Toshikatsu and Takahashi, Nozomi and Kernbauer, Elisabeth and Demir{\"o}z, Duygu and Lang, Michaela and Superti-Furga, Giulio and Decker, Thomas and Pichler, Andrea and Ikeda, Fumiyo and Kroemer, Guido and Vandenabeele, Peter and Sorensen, Poul H and Penninger, Josef M},
  issn         = {2211-1247},
  journal      = {CELL REPORTS},
  keyword      = {INDUCED APOPTOSIS,UBIQUITIN SYSTEM,ADAPTIVE IMMUNITY,PROGRAMMED NECROSIS,CASPASE-8 ACTIVATION,NF-KAPPA-B,DEXTRAN SODIUM-SULFATE,NECROSIS-FACTOR,TNF-ALPHA,CANCER-THERAPY},
  language     = {eng},
  number       = {7},
  pages        = {1481--1492},
  title        = {The tumor suppressor Hace1 is a critical regulator of TNFR1-mediated cell fate},
  url          = {http://dx.doi.org/10.1016/j.celrep.2016.04.032},
  volume       = {15},
  year         = {2016},
}

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