Dominant negative FADD dissipates the proapoptotic signalosome of the unfolded protein response in diabetic embryopathy

Am J Physiol Endocrinol Metab. 2015 Nov 15;309(10):E861-73. doi: 10.1152/ajpendo.00215.2015. Epub 2015 Sep 29.


Endoplasmic reticulum (ER) stress and caspase 8-dependent apoptosis are two interlinked causal events in maternal diabetes-induced neural tube defects (NTDs). The inositol-requiring enzyme 1α (IRE1α) signalosome mediates the proapoptotic effect of ER stress. Diabetes increases tumor necrosis factor receptor type 1R-associated death domain (TRADD) expression. Here, we revealed two new unfolded protein response (UPR) regulators, TRADD and Fas-associated protein with death domain (FADD). TRADD interacted with both the IRE1α-TRAF2-ASK1 complex and FADD. In vivo overexpression of a FADD dominant negative (FADD-DN) mutant lacking the death effector domain disrupted diabetes-induced IRE1α signalosome and suppressed ER stress and caspase 8-dependent apoptosis, leading to NTD prevention. FADD-DN abrogated ER stress markers and blocked the JNK1/2-ASK1 pathway. Diabetes-induced mitochondrial translocation of proapoptotic Bcl-2 members mitochondrial dysfunction and caspase cleavage were also alleviated by FADD-DN. In vitro TRADD overexpression triggered UPR and ER stress before manifestation of caspase 3 and caspase 8 cleavage and apoptosis. FADD-DN overexpression repressed high glucose- or TRADD overexpression-induced IRE1α phosphorylation, its downstream proapoptotic kinase activation and endonuclease activities, and apoptosis. FADD-DN also attenuated tunicamycin-induced UPR and ER stress. These findings suggest that TRADD participates in the IRE1α signalosome and induces UPR and ER stress and that the association between TRADD and FADD is essential for diabetes- or high glucose-induced UPR and ER stress.

Keywords: apoptosis; dominant negative Fas-associated protein with death domain; endoplasmic reticulum stress; maternal diabetes; neural tube defects; unfolded protein response.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Biomarkers / metabolism
  • Cell Line
  • Diabetes Mellitus, Experimental / physiopathology
  • Down-Regulation*
  • Embryo, Mammalian / metabolism
  • Embryo, Mammalian / pathology
  • Endoplasmic Reticulum Stress
  • Endoribonucleases / metabolism
  • Fas-Associated Death Domain Protein / genetics
  • Fas-Associated Death Domain Protein / metabolism*
  • Female
  • Humans
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Multienzyme Complexes / metabolism
  • Mutant Proteins / metabolism
  • Neural Tube Defects / embryology
  • Neural Tube Defects / etiology*
  • Neural Tube Defects / metabolism
  • Neural Tube Defects / pathology
  • Neurogenesis*
  • Pregnancy
  • Pregnancy in Diabetics / physiopathology*
  • Protein Serine-Threonine Kinases / metabolism
  • Recombinant Fusion Proteins / metabolism
  • TNF Receptor-Associated Death Domain Protein / genetics
  • TNF Receptor-Associated Death Domain Protein / metabolism
  • Unfolded Protein Response*


  • Biomarkers
  • Ern1 protein, rat
  • FADD protein, human
  • Fas-Associated Death Domain Protein
  • Multienzyme Complexes
  • Mutant Proteins
  • Recombinant Fusion Proteins
  • TNF Receptor-Associated Death Domain Protein
  • Tradd protein, mouse
  • Protein Serine-Threonine Kinases
  • Endoribonucleases