Regulation of FADD phosphorylation is crucial for growth and proliferation

摘要

Fas associated death domain protein (FADD) is an adapter protein known to transmit apoptotic signals from death domain-containing members of the tumor necrosis factor receptor (TNF-R) family. However, characterization of FADD-deficient lymphocytes showed that FADD is also crucial for lymphocyte development and proliferation. Previous studies have shown that FADD-deficient T cells exhibit disarray of cell cycle machinery. Phosphorylation of FADD is G_2/M-specific but its significance is not clear. Here, we generated mice bearing a Ser→Ala or Ser→Asp mutation in the FADD phosphorylation site (serine 191) located outside the death effector-and death-domains to investigate the function of FADD phosphorylation in vivo. In these mice, Fas-mediated apoptosis is unimpaired. While FADD (S191A) mice exhibit no apparent defects, FADD (S191D) mice exhibit many immune developmental problems similar to FADD- deficiency. Furthermore, FADD (S191D) mice are runted, anemic and exhibit splenomegaly but not T-cell autoimmunity. Alignment of FADD proteins shows a remarkable conservation of S191 among mammalian proteins but this region is absent in lower organisms.