FADD in the Nucleus

Science's STKE  13 May 2003:
Vol. 2003, Issue 182, pp. tw191-TW191
DOI: 10.1126/stke.2003.182.tw191

Adaptor proteins that link cell-surface receptors to intracellular signaling cascades most likely reside in the cytoplasm, ready for action. However, Screaton et al. propose that an adaptor called Fas-associated death domain protein (FADD), which links the Fas death receptor at the cell surface to intracellular initiator caspases, is primarily located in the nucleus, despite its lack of a nuclear localization signal. This was observed in several adherent cell lines by immunofluorescent staining and cell fractionation. Cell detachment from extracellular matrix caused FADD to exit the nucleus and associate with Fas, which may account for the increased sensitivity of suspended cells to Fas ligand. Mutation of a known serine phosphorylation site in FADD inhibited its nuclear localization, and the authors propose that the direct interaction observed between a nuclear shuttle protein called exportin-5 and FADD could underlie an active transport system that responds to death receptor stimulation. Furthermore, a yeast two-hybrid screen revealed a FADD interaction with a DNA-repair protein called methyl-CpG binding domain protein 4 (MBD4). Mice or fibroblast cells lacking MBD4 showed modified sensitivities to Fas stimulation. The study implies a possible functional connection between genome surveillance, DNA repair, and apoptosis.

R. A. Screaton, S. Kiessling, O. J. Sansom, C. B. Millar, K. Maddison, A. Bird, A. R. Clarke, S. M. Frisch, Fas-associated death domain protein interacts with methyl-CpG binding domain protein 4: A potential link between genome surveillance and apoptosis. Proc. Natl. Acad. Sci. U.S.A. 100, 5211-5216 (2003). [Abstract] [Full Text]