BCL-XL regulates TNF-α-mediated cell death independently of NF-κB, FLIP and IAPs
Solé Serra, Carme
Llecha Cano, Núria
Segura Ginard, Miguel Francisco
Moubarak, Rana S.
Iglesias Guimarais, Victoria
Pérez García, María José
Rodríguez Álvarez, José
Yuste Mateos, Víctor J. (Víctor José)
Comella i Carnicé, Joan Xavier
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Upon activation, tumor necrosis factor alpha (TNF-α) receptor can engage apoptotic or survival pathways. Inhibition of macromolecular synthesis is known to sensitize cells to TNF-α-induced cell death. It is believed that this sensitization is due to the transcriptional blockade of genes regulated by NF-κB. Nevertheless, such evidence has remained elusive in the nervous system. Here, we show that TNF-α cannot normally induce apoptosis in PC12 cells or cortical neurons. However, cells treated with Actinomycin D (ActD) become susceptible to TNF-α-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-α receptor signaling showed no significant downregulation of NF-κB target genes, such as IAPs or FLIP, under such conditions. However, Bcl-xL protein levels, but not those of Bcl-2, Bax and Bak, are reduced by ActD or TNF-α/ ActD treatments. Moreover, Bcl-xL overexpression fully protects cells against TNF-α/ActD-induced cell death. When endogenous levels of Bcl-xL are specifically downregulated by lentiviral-based RNAi, cells no longer require ActD to be sensitive to TNF-α-triggered apoptosis. Furthermore, Bcl-xL downregulation does not affect TNF-α-mediated NF-κB activation. Altogether, our results demonstrate that Bcl-xL, and not Bcl-2, FLIP or IAPs, acts as the endogenous regulator of neuronal resistance/sensitivity to TNF-α-induced apoptosis in an NF-κB-independent manner.