Nuclear localization of DEDD leads to caspase-6 activation through its death effector domain and inhibition of RNA polymerase I dependent transcription

O. Schickling, A. H. Stegh, J. Byrd, M. E. Peter*

*Corresponding author for this work

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

The death effector domain (DED) is a protein/protein interaction domain only found in proteins that are involved in apoptosis signaling. DEDD is a novel apoptosis signaling molecule that carries an N-terminal DED with complete sequence identity between the murine, rat, bovine and human domains. We previously identified two nuclear localization signals (NLS) responsible for DEDDs nuclear localization when transiently expressed. Using a new anti-DEDD antibody that allows us to stain endogenous DEDD in immunofluorescence microscopy we now detect a significant amount of DEDD in nucleoli of all cells tested. When overexpressed, DEDD localizes to nucleoli-like structures, activates caspase-6 and specifically inhibits RNA polymerase I (Pol I) dependent transcription in vivo as shown by blockage of BrUTP incorporation. The DED in DEDD is sufficient for its DNA binding, caspase-6 activating and Pol I specific transcriptional repressor activity. We have identified a third NLS in DEDD and only mutation of all three NLS generated a protein, DEDDΔNLS1-3, that mainly localized to the cytoplasm. This protein no longer induced apoptosis, indicating that in contrast to other DED proteins, such as FADD, caspase-8 or c-FLIP, DEDD induces apoptosis from within the nucleus. This effect is abolished when specific point mutations are made within the DED. The DED in DEDD therefore represents a novel domain that is structurally similar to other DEDs but functionally different from classical DEDs found in FADD or caspase-8.

Original languageEnglish (US)
Pages (from-to)1157-1168
Number of pages12
JournalCell Death and Differentiation
Volume8
Issue number12
DOIs
StatePublished - Dec 1 2001

Keywords

  • Apoptosis
  • Caspase-6
  • DEDD
  • Nucleolus
  • rDNA transcription

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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