Subcellular compartmentalization of FADD as a new level of regulation in death receptor signaling.
Fas-associated protein with death domain (FADD) is an essential adaptor protein in death receptor-mediated signal transduction. During apoptotic signaling, FADD functions in the cytoplasm, where it couples activated receptors with initiator caspase-8. However, in resting cells, FADD is predominantly stored in the nucleus. In this study, we examined the modalities of FADD intracellular trafficking. We demonstrate that, upon CD95 activation, FADD redistributes from the nucleus to the cytoplasm. This inducible nuclear-cytoplasmic translocation of FADD is independent of CD95 internalization, formation of the death-inducing signaling complex, and caspase-8 activation. In contrast to nuclear export of FADD, its subsequent recruitment and accumulation at endosomes containing internalized CD95 requires a caspase-8-dependent feedback loop. These data indicate the existence of differential pathways directing FADD nuclear export and cytoplasmic trafficking, and identify subcellular compartmentalization of FADD as a novel regulatory mechanism in death receptor signaling.
Föger
Niko
N
Department of Immunology and Cell Biology, Research Center Borstel, Leibniz Center for Medicine and Biosciences, Germany.
Bulfone-Paus
Silvia
S
Chan
Andrew C
AC
Lee
Kyeong-Hee
KH
D017209:Apoptosis / Q000502:physiology; D002051:Burkitt Lymphoma; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology; D011992:Endosomes / Q000502:physiology; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism / Q000502:physiology; D053218:Receptors, Death Domain / Q000502:physiology*; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology
D053200:Fas-Associated Death Domain Protein; D009363:Neoplasm Proteins; D053218:Receptors, Death Domain; D053221:TNF-Related Apoptosis-Inducing Ligand; D053181:Caspase 8