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Nat Immunol. 2009 Aug;10(8):918-26. doi: 10.1038/ni.1754. Epub 2009 Jul 13.

A TNF- and c-Cbl-dependent FLIP(S)-degradation pathway and its function in Mycobacterium tuberculosis-induced macrophage apoptosis.

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Department of Chemistry, Bose Institute, Kolkata, India.


Apoptosis is central to the interaction between pathogenic mycobacteria and host macrophages. Caspase-8-dependent apoptosis of infected macrophages, which requires activation of the mitogen-activated protein (MAP) kinase p38, lowers the spread of mycobacteria. Here we establish a link between the release of tumor necrosis factor (TNF) and mycobacteria-mediated macrophage apoptosis. TNF activated a pathway involving the kinases ASK1, p38 and c-Abl. This pathway led to phosphorylation of FLIP(S), which facilitated its interaction with the E3 ubiquitin ligase c-Cbl. This interaction triggered proteasomal degradation of FLIP(S), which promoted activation of caspase-8 and apoptosis. Our findings identify a previously unappreciated signaling pathway needed for Mycobacterium tuberculosis-triggered macrophage cell death.

[Indexed for MEDLINE]

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