Inhibition of the NF-κB survival pathway via caspase-dependent cleavage of the IKK complex scaffold protein and NF-κB essential modulator NEMO
| Autor: | Patrick Auberger, Virginie Bottero, Klaus Schulze-Osthoff, Véronique Imbert, N Gonthier, Catherine Frelin, Ajoy K. Samraj, J F Peyron, G Courtois |
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| Rok vydání: | 2007 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Programmed cell death Cell Survival Apoptosis Jurkat cells Jurkat Cells medicine Humans Staurosporine skin and connective tissue diseases Molecular Biology Caspase biology Tumor Necrosis Factor-alpha NF-kappa B I-Kappa-B Kinase Cell Biology NFKB1 Molecular biology I-kappa B Kinase Cell biology Enzyme Activation Caspases biology.protein Signal transduction Signal Transduction medicine.drug |
| Zdroj: | Cell Death & Differentiation. 15:152-160 |
| ISSN: | 1476-5403 1350-9047 |
| DOI: | 10.1038/sj.cdd.4402240 |
| Popis: | Apoptosis is mediated by cysteine-dependent, aspartate-directed proteases of the caspase family that proteolyse strategic intracellular substrates to induce cell suicide. We describe here that engagement of apoptotic processes by Fas triggering or by staurosporine stimulation leads to the caspase-dependent inactivation of the nuclear factor kappa B (NF-kappaB) pathway after cleavage of IKK1 (IkappaB kinase 1) and NEMO (NF-kappaB essential modulator), which are needed to transduce NF-kappaB activation signals. In this study, we have analyzed in more detail, the role of NEMO cleavage, as NEMO, but not IKK1, is important for the pro-survival actions of NF-kappaB. We demonstrate that NEMO is cleaved after Asp355 to remove the last 64 C-terminal amino acids. This short form was unable to rescue NF-kappaB activation by tumor necrosis factor-alpha (TNF-alpha) when transfected in NEMO-deficient cells. Consequently, inactivation of NEMO resulted in an inhibition of the expression of antiapoptotic NF-kappaB-target genes coding for caspase inhibitors (cIAP-1, cIAP-2) or adaptors of the TNF receptor family. NEMO-deficient Jurkat cells transiently expressing a non-cleavable mutant of NEMO were less sensitive to TNF-alpha-induced apoptosis. Therefore, downmodulation of NF-kappaB activation via the proteolytic cleavage of NEMO could represent an amplification loop for apoptosis. |
| Databáze: | OpenAIRE |
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