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. 2008 Oct;18(10):1020-36.
doi: 10.1038/cr.2008.76.

BCL-XL regulates TNF-alpha-mediated cell death independently of NF-kappaB, FLIP and IAPs

Raffaella Gozzelino  1 , Carme Sole, Nuria Llecha, Miguel F Segura, Rana S Moubarak, Victoria Iglesias-Guimarais, M Jose Perez-Garcia, Stephanie Reix, Jisheng Zhang, Nahuai Badiola, Daniel Sanchis, Jose Rodriguez-Alvarez, Ramon Trullas, Victor J Yuste, Joan X Comella
Affiliations

BCL-XL regulates TNF-alpha-mediated cell death independently of NF-kappaB, FLIP and IAPs

Raffaella Gozzelino et al. Cell Res. 2008 Oct.

Abstract

Upon activation, tumor necrosis factor alpha (TNF-alpha) receptor can engage apoptotic or survival pathways. Inhibition of macromolecular synthesis is known to sensitize cells to TNF-alpha-induced cell death. It is believed that this sensitization is due to the transcriptional blockade of genes regulated by NF-kappaB. Nevertheless, such evidence has remained elusive in the nervous system. Here, we show that TNF-alpha cannot normally induce apoptosis in PC12 cells or cortical neurons. However, cells treated with Actinomycin D (ActD) become susceptible to TNF-alpha-induced cell death through the activation of caspase-8, generation of tBid and activation of caspase-9 and -3. Analysis of several proteins involved in TNF-alpha receptor signaling showed no significant downregulation of NF-kappaB target genes, such as IAPs or FLIP, under such conditions. However, Bcl-x(L) protein levels, but not those of Bcl-2, Bax and Bak, are reduced by ActD or TNF-alpha/ActD treatments. Moreover, Bcl-x(L) overexpression fully protects cells against TNF-alpha/ActD-induced cell death. When endogenous levels of Bcl-x(L) are specifically downregulated by lentiviral-based RNAi, cells no longer require ActD to be sensitive to TNF-alpha-triggered apoptosis. Furthermore, Bcl-x(L) downregulation does not affect TNF-alpha-mediated NF-kappaB activation. Altogether, our results demonstrate that Bcl-x(L), and not Bcl-2, FLIP or IAPs, acts as the endogenous regulator of neuronal resistance/sensitivity to TNF-alpha-induced apoptosis in an NF-kappaB-independent manner.

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