User Manual Privacy Policy Disclaimer Contact us
  Advanced SearchBrowse




Journal Article

The Tumor Suppressor Hace1 is a critical regulator TNFR1-mediated cell fate


Pichler,  Andrea
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

There are no locators available
Fulltext (public)
There are no public fulltexts available
Supplementary Material (public)
There is no public supplementary material available

Tortola, L., Nitsch, R., Bertrand, M. J., Kogler, M., Redouane, Y., Kozieradzki, I., et al. (2016). The Tumor Suppressor Hace1 is a critical regulator TNFR1-mediated cell fate. Cell Reports, 1481-1492. doi:10.1016/j.celrep.2016.08.072.

Cite as: http://hdl.handle.net/11858/00-001M-0000-002C-C323-8
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.