Daxx plays a novel role in T cell survival but is dispensable in Fas-induced apoptosis

• Published in: PloS one 2017-03, Vol.12 (3), p.e0174011-e0174011
• Main Authors: Li, Jinghe, Qian, Liangyue, Dowling, John P, Curcione, Christine, Kurup, Drishya, Zhang, Jianke
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Apoptosis; Apoptosis - physiology; Binding proteins; Biology and Life Sciences; Carrier Proteins - metabolism; Carrier Proteins - physiology; Caspase; Caspase-8; Cell activation; Cell death; Cell Proliferation; Cell survival; Cell Survival - physiology; Clonal deletion; Conditional mutant; Daxx protein; Embryos; FADD protein; Fas antigen; fas Receptor - metabolism; Flow Cytometry; Gene mutation; Genetic aspects; Homeostasis; Hyperplasia; Immune system; Intracellular Signaling Peptides and Proteins - metabolism; Intracellular Signaling Peptides and Proteins - physiology; Kinases; Lethality; Lymphocytes; Lymphocytes T; MAP kinase; Medicine and Health Sciences; Mice; Mice, Transgenic; Mutation; Nuclear Proteins - metabolism; Nuclear Proteins - physiology; Organs; Proteins; Research and Analysis Methods; Rodents; Survival; T cell receptors; T cells; T-cell receptor; T-Lymphocytes - cytology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0174011

Daxx was originally isolated as a Fas-binding protein. However, the in vivo function of Daxx in Fas-induced apoptosis has remained enigmatic. Fas plays an important role in homeostasis in the immune system. Fas gene mutations lead to autoimmune-lymphoproliferation (lpr) diseases characterized by hyperplasia of secondary lymphoid organs. It is well established that the FADD adaptor binds to Fas, and recruits/activates caspase 8. However, additional proteins including Daxx have also been indicated to associate with Fas. It was proposed that Daxx mediates a parallel apoptotic pathway that is independent of FADD and caspase 8, but signals through ASK1-mediated apoptotic pathway. However, because the deletion of Daxx leads to embryonic lethality, the in vivo function of Daxx has not been properly analyzed. In the current study, analysis was performed using a conditional mutant mouse in which Daxx was deleted specifically in T cells. The data show that Daxx-/- T cells were able to undergo normal Fas-induced apoptosis. While containing normal thymocyte populations, the T cell-specific Daxx-/- mice have a reduced peripheral T cell pool. Importantly, Daxx-deficient T cells displayed increased death responses upon activation through TCR stimulation. These results unequivocally demonstrated that Daxx does not mediate Fas-induced apoptosis, but rather that it plays a critical role in survival responses in primary mature T cells.