title: The death effector domain-associated factor plays distinct regulatory roles in the nucleus and cytoplasm.
abstract: Homophilic interactions of death effector domains (DEDs) are crucial for the signaling pathways of death receptor-mediated apoptosis. The machinery that regulates proper oligomerization and autoactivation of procaspase-8 and/or procaspase-10 during T lymphocyte activation determines whether the cells will undergo caspase-mediated apoptosis or proliferation. We screened a yeast two-hybrid library by using the DEDs contained in the prodomains of procaspase-8 and procaspase-10 and isolated a DED-associated factor (DEDAF) that interacts with several DED-containing proteins but does not itself contain a DED. DEDAF is highly conserved between human and mouse (98% amino acid identity) and is homologous to a nuclear regulatory protein YAF-2. DEDAF is expressed at the highest levels in lymphoid tissues and placenta. DEDAF interacts with FADD, procaspase-8, and procaspase-10 in the cytosol as well as with the DED-containing DNA-binding protein (DEDD) in the nucleus. At the cell membrane, DEDAF augmented the formation of CD95-FADD-caspase-8 complexes and enhanced death receptor- as well as DED-mediated apoptosis. In the nucleus, DEDAF caused the DEDD protein to relocalize from subnuclear structures to a diffuse distribution in the nucleoplasm. Our data therefore suggest that DEDAF may be involved in the regulation of both cytoplasmic and nuclear events of apoptosis.
authors.affiliation: Laboratory of Immunology, NIAID, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: L
authors.initials: L
authors.lastname: Zheng
authors.forename: O
authors.initials: O
authors.lastname: Schickling
authors.forename: M E
authors.initials: ME
authors.lastname: Peter
authors.forename: M J
authors.initials: MJ
authors.lastname: Lenardo
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis / Q000502:physiology; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D053455:Caspase 10; D020169:Caspases / Q000737:chemistry; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D003001:Cloning, Molecular; D003593:Cytoplasm / Q000378:metabolism*; D018076:DNA, Complementary; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D011485:Protein Binding; D012097:Repressor Proteins; D017386:Sequence Homology, Amino Acid
chemical_list: D002352:Carrier Proteins; D018076:DNA, Complementary; D047908:Intracellular Signaling Peptides and Proteins; C434957:RYBP protein, human; D012097:Repressor Proteins; D053455:Caspase 10; D020169:Caspases; C506438:CASP10 protein, human