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

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

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Department of Obstetrics, Gynecology, and Reproductive Sciences.
Department of Medicine.
Cell Biology Group, Department of Surgery, and.
Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland; and.
Department of Obstetrics, Gynecology, and Reproductive Sciences, Institut de Biologie de Valrose, UMR CNRS 7277, UMR Institut National de la Sante et de la Recherche Medicale 1091, Université de Nice-Sophia-Antipolis, Nice, France


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.


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

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