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

Cell Rep. 2016 May 17;15(7):1481-1492. doi: 10.1016/j.celrep.2016.04.032. Epub 2016 May 5.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Caspase 8 / metabolism
  • Cell Lineage* / drug effects
  • Colitis / metabolism
  • Colitis / pathology
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • Dextran Sulfate
  • Embryo, Mammalian / cytology
  • Enzyme Activation / drug effects
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Gene Deletion
  • Mice, Inbred C57BL
  • Mutation / genetics
  • NF-kappa B / metabolism
  • Necrosis
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
  • Receptors, Tumor Necrosis Factor, Type I / metabolism*
  • TNF Receptor-Associated Factor 2 / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology
  • Tumor Suppressor Proteins / metabolism*
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination / drug effects


  • NF-kappa B
  • Receptors, Tumor Necrosis Factor, Type I
  • TNF Receptor-Associated Factor 2
  • Tnfrsf1a protein, mouse
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Proteins
  • Dextran Sulfate
  • HACE1 protein, mouse
  • Ubiquitin-Protein Ligases
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk3 protein, mouse
  • Caspase 8