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

Luigi Tortola, Roberto Nitsch, Mathieu Bertrand UGent, Melanie Kogler, Younes Redouane, Ivona Kozieradzki, Iris Uribesalgo, Lilian M Fennell, Mads Daugaard, Helene Klug, et al. (2016) CELL REPORTS. 15(7). p.1481-1492
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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
INDUCED APOPTOSIS, UBIQUITIN SYSTEM, ADAPTIVE IMMUNITY, PROGRAMMED NECROSIS, CASPASE-8 ACTIVATION, NF-KAPPA-B, DEXTRAN SODIUM-SULFATE, NECROSIS-FACTOR, TNF-ALPHA, CANCER-THERAPY
journal title
CELL REPORTS
Cell Reports
volume
15
issue
7
pages
1481 - 1492
Web of Science type
Article
Web of Science id
000376165300012
JCR category
CELL BIOLOGY
JCR impact factor
8.282 (2016)
JCR rank
26/189 (2016)
JCR quartile
1 (2016)
ISSN
2211-1247
DOI
10.1016/j.celrep.2016.04.032
language
English
UGent publication?
yes
classification
A1
additional info
corrrection (missing author) published in: Cell Reports (2016) 16(12), 3414 ; DOI 10.1016/j.celrep.2016.08.072 (uploaded document is corrected version)
copyright statement
Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
id
7250178
handle
http://hdl.handle.net/1854/LU-7250178
date created
2016-06-13 10:31:51
date last changed
2017-07-24 13:55:34
@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},
}

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.