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- Title
A TNF- and c-Cbl-dependent FLIP<sub>S</sub>-degradation pathway and its function in Mycobacterium tuberculosis–induced macrophage apoptosis.
- Authors
Kundu, Manikuntala; Pathak, Sushil Kumar; Kumawat, Kuldeep; Basu, Sanchita; Chatterjee, Gargi; Pathak, Shresh; Noguchi, Takuya; Takeda, Kohsuke; Ichijo, Hidenori; Thien, Christine B. F.; Langdon, Wallace Y.; Basu, Joyoti
- Abstract
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 FLIPS, which facilitated its interaction with the E3 ubiquitin ligase c-Cbl. This interaction triggered proteasomal degradation of FLIPS, which promoted activation of caspase-8 and apoptosis. Our findings identify a previously unappreciated signaling pathway needed for Mycobacterium tuberculosis–triggered macrophage cell death.
- Subjects
APOPTOSIS; MYCOBACTERIA; MACROPHAGES; MITOGENS; TUMOR necrosis factors; PHOSPHORYLATION
- Publication
Nature Immunology, 2009, Vol 10, Issue 8, p918
- ISSN
1529-2908
- Publication type
Article
- DOI
10.1038/ni.1754