The C-terminal domain of A1/Bfl-1 regulates its anti-inflammatory function in human endothelial cells

Renata P. Guedes, Eduardo Rocha, Jerome Mahiou, Herwig P. Moll, Maria B. Arvelo, Janis M. Taube, Clayton R. Peterson, Elzbieta Kaczmarek, Christopher R. Longo, Cleide G. da Silva, Christiane Ferran

Research output: Contribution to journalArticle

Abstract

A1/Bfl-1 is a NF-κB dependent, anti-apoptotic Bcl-2 family member that contains four Bcl-2 homology domains (BH) and an amphipathic C-terminal domain, and is expressed in endothelial cells (EC). Based on NF-κB reporter assays in bovine aortic EC, we have previously demonstrated that A1, like Bcl-2 and Bcl-xL, inhibits NF-κB activation. These results, however, do not fully translate when evaluating the cell's own NF-κB machinery in human EC overexpressing A1 by means of recombinant adenovirus (rAd.) mediated gene transfer. Indeed, overexpression of full-length A1 in human umbilical vein EC (HUVEC), and human dermal microvascular EC (HDMEC) failed to inhibit NF-κB activation. However, overexpression of a mutant lacking the C-terminal domain of A1 (A1δC) demonstrated a potent NF-κB inhibitory effect in these cells. Disparate effects of A1 and A1δC on NF-κB inhibition in human EC correlated with mitochondrial (A1) versus non-mitochondrial (A1δC) localization. In contrast, both full-length A1 and A1δC protected EC from staurosporine (STS)-induced cell death, indicating that mitochondrial localization was not necessary for A1's cytoprotective function in human EC. In conclusion, our data uncover a regulatory role for the C-terminal domain of A1 in human EC: anchoring A1 to the mitochondrion, which conserves but is not necessary for its cytoprotective function, or by its absence freeing A1 from the mitochondrion and uncovering an additional anti-inflammatory effect.

Original languageEnglish (US)
Pages (from-to)1553-1561
Number of pages9
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1833
Issue number6
DOIs
StatePublished - Jun 1 2013

Keywords

  • A1/Bfl-1
  • Apoptosis
  • C-terminal domain
  • Mitochondria
  • Nuclear Factor Kappa-B

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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  • Cite this

    Guedes, R. P., Rocha, E., Mahiou, J., Moll, H. P., Arvelo, M. B., Taube, J. M., Peterson, C. R., Kaczmarek, E., Longo, C. R., da Silva, C. G., & Ferran, C. (2013). The C-terminal domain of A1/Bfl-1 regulates its anti-inflammatory function in human endothelial cells. Biochimica et Biophysica Acta - Molecular Cell Research, 1833(6), 1553-1561. https://doi.org/10.1016/j.bbamcr.2013.03.001