Human transcription factor IIIC (TFIIIC) is a multi-subunit transcriptional complex that recognizes the promoters for transfer RNA and virus-associated RNA genes. According to a report in Cell Death and Differentiation, it also turns out to be an unexpected binding partner for a newly discovered death-effector domain (DED) protein — FLAME-3.
Emad Alnemri and colleagues identified FLAME-3 in a search for sequences homologous to DED-containing proteins, which are important in death-receptor signalling. FLAME-3 shows almost 50% identity to another DED-containing protein, DEDD, and both proteins are localized to the nucleus. Co-immunoprecipitation experiments showed that the two proteins can form homo- and heterodimers, and that they can both also bind to cellular FLIP (c-FLIP), a protein that antagonizes the death-receptor pathway.
The authors next carried out a yeast two-hybrid screen for other proteins that interact with DEDD, and pulled out the TFIIIC102 subunit of TFIIIC. Co-immunoprecipitation and GST-pulldown experiments confirmed that TFIIIC102 interacts with both DEDD and FLAME-3 in vitro. Alnemri and colleagues then co-transfected cells with green fluorescent protein (GFP)-tagged TFIIIC102 and DEDD or FLAME-3. In both cases, the TFIIIC102 relocalized from the cytoplasm to the nucleus, hinting that DEDD and FLAME-3 could act as chaperones to translocate TFIIIC102 across the nuclear membrane.
Finally, the authors showed that overexpression of DEDD or FLAME-3 can inhibit the transcriptional machinery, perhaps by sequestering TFIIIC102, consistent with a role for these proteins in regulating TFIIIC.
ORIGINAL RESEARCH PAPER
Zhan, Y. et al. Death effector domain-containing proteins DEDD and FLAME-3 form nuclear complexes with the TFIIIC102 subunit of human transcription factor IIIC. Cell Death Diff. 9, 439–447 (2002)
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Mitchell, A. Deadly FLAME. Nat Rev Mol Cell Biol 3, 229 (2002). https://doi.org/10.1038/nrm791
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DOI: https://doi.org/10.1038/nrm791