NF-κB protects from the lysosomal pathway of cell death

Ni Liu, Srikumar M. Raja, Francesca Zazzeroni, Sunil S. Metkar, Ramila Shah, Manling Zhang, Yue Wang, Dieter Brömme, William A. Russin, Justine C. Lee, Marcus E. Peter, Christopher J. Froelich, Guido Franzoso, Philip G. Ashton-Rickardt*

*Corresponding author for this work

Research output: Contribution to journalArticle

100 Scopus citations

Abstract

The programme of gene expression induced by RelA/NF-κB transcription factors is critical to the control of cell survival. Ligation of 'death receptors' such as tumor necrosis factor receptor 1 (TNF-R1) triggers apoptosis, as well as NF-κB, which counteracts this process by activating the transcription of anti-apoptotic genes. In addition to activating caspases, TNF-R1 stimulation causes the release of cathepsins, most notably cathepsin B, from the lysosome into the cytoplasm where they induce apoptosis. Here we report a mechanism by which NF-κB protects cells against TNF-α-induced apoptosis: inhibition of the lysosomal pathway of apoptosis. NF-κB can protect cells from death after TNF-R1 stimulation, by extinguishing cathepsin B activity in the cytosol. This activity of NF-κB is mediated, at least in part, by the upregulation of Serine protease inhibitor 2A (Spi2A), a potent inhibitor of cathepsin B. Indeed, Spi2A can substitute for NF-κB in suppressing the induction of cathepsin B activity in the cytosol. Thus, inhibition of cathepsin B by Spi2A is a mechanism by which NF-κB protects cells from lysosome-mediated apoptosis.

Original languageEnglish (US)
Pages (from-to)5313-5322
Number of pages10
JournalEMBO Journal
Volume22
Issue number19
DOIs
StatePublished - Oct 1 2003

Keywords

  • Apoptosis
  • Cathepsin
  • Lysosome
  • NF-κB
  • Serpin

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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  • Cite this

    Liu, N., Raja, S. M., Zazzeroni, F., Metkar, S. S., Shah, R., Zhang, M., Wang, Y., Brömme, D., Russin, W. A., Lee, J. C., Peter, M. E., Froelich, C. J., Franzoso, G., & Ashton-Rickardt, P. G. (2003). NF-κB protects from the lysosomal pathway of cell death. EMBO Journal, 22(19), 5313-5322. https://doi.org/10.1093/emboj/cdg510