DEDD, A NOVEL DEATH EFFECTOR DOMAIN-CONTAINING PROTEIN, TARGETED TO THE NUCLEOLUS

The CD95 signaling pathway comprises proteins that contain one or two death effector domains (DED), such as FADD/Mort1 or caspase-8, Here we describe a novel 37 kDa protein, DEDD, that contains an N-terminal DE D, DEDD is highly conserved between human and mouse (98.7% identity) a nd is ubiquitously expressed. Overexpression of DEDD in 293T cells ind uced weak apoptosis, mainly through its DED by which it interacts with FADD and caspase-8, Endogenous DEDD was found in the cytoplasm and tr anslocated into the nucleus upon stimulation of CD95, Immunocytologica l studies revealed that overexpressed DEDD directly translocated into the nucleus, where it co-localizes in the nucleolus with UBF, a basal factor required for RNA polymerase I transcription. Consistent with it s nuclear localization, DEDD contains two nuclear localization signals and the C-terminal part shares sequence homology with histones, Recom binant DEDD binds to both DNA and reconstituted mononucleosomes and in hibits transcription in a reconstituted in vitro system. The results s uggest that DEDD is a final target of a chain of events by which the C D95-induced apoptotic signal is transferred into the nucleolus to shut off cellular biosynthetic activities.