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A TNF- and c-Cbl-dependent FLIPS-degradation pathway and its function in Mycobacterium tuberculosis–induced macrophage apoptosis

Nature Immunology volume 10, pages 918–926 (2009)Cite this article

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.

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Figure 1: ASK1, p38 and TNF influence M. tuberculosis–mediated macrophage apoptosis.
Figure 2: TNF induces ASK1- and p38-dependent phosphorylation of FLIPS and subsequent FLIPS degradation.
Figure 3: TNF-induced ubiquitination of FLIPS is dependent on its phosphorylation.
Figure 4: Phosphorylation of FLIPS and induction of ubiquitination of FLIPS by c-Abl.
Figure 5: Ubiquitination and degradation of FLIPS requires c-Cbl.
Figure 6: TNF induces c-Cbl-mediated degradation of FLIPS and activation of caspase-8.
Figure 7: TNF-induced apoptosis of macrophages requires c-Cbl.
Figure 8: M. tuberculosis–induced macrophage apoptosis depends on c-Cbl.

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Acknowledgements

We thank R. Davis (University of Massachusetts Medical School) for Flag-tagged p38 and p38(dn) and for Jnk and its dominant negative mutant; J. Han (Scripps Research Institute) for bacterial MKK6(E) and p38 constructs; and G. Superti-Furga (Austrian Academy of Science) for c-Abl and kinase-inactive c-Abl in pSGT. Supported by the Council of Scientific and Industrial Research of the Government of India (S.K.P.) and the Department of Science and Technology of the Government of India (J.B.).

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Authors and Affiliations

  1. Department of Chemistry, Bose Institute, Kolkata, India

    Manikuntala Kundu, Sushil Kumar Pathak, Kuldeep Kumawat, Sanchita Basu, Gargi Chatterjee, Shresh Pathak & Joyoti Basu

  2. Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan

    Takuya Noguchi, Kohsuke Takeda & Hidenori Ichijo

  3. School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia

    Christine B F Thien & Wallace Y Langdon

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Contributions

M.K. designed and did research, analyzed data and wrote the paper; S.K.P., K.K., S.B., G.C. and S.P. did research; T.N., K.T., H.I., C.B.F.T. and W.Y.L. contributed tools; and J.B. designed the research, analyzed data and wrote the paper.

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Correspondence to Joyoti Basu.

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Kundu, M., Pathak, S., Kumawat, K. et al. A TNF- and c-Cbl-dependent FLIPS-degradation pathway and its function in Mycobacterium tuberculosis–induced macrophage apoptosis. Nat Immunol 10, 918–926 (2009). https://doi.org/10.1038/ni.1754

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