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

M. Kundu, S.K. Pathak, K. Kumawat, S. Basu, G. Chatterjee, S. Pathak, T. Noguchi, K. Takeda, H. Ichijo, Christine Thien, Wallace Langdon, J. Basu

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    56 Citations (Scopus)

    Abstract

    Apoptosis is central to the interaction between pathogenic mycobacteria and host macrophages. Caspase-8-dependent apoptosisof infected macrophages, which requires activation of the mitogen-activated protein (MAP) kinase p38, lowers the spreadof mycobacteria. Here we establish a link between the release of tumor necrosis factor (TNF) and mycobacteria-mediatedmacrophage apoptosis. TNF activated a pathway involving the kinases ASK1, p38 and c-Abl. This pathway led tophosphorylation of FLIPS, which facilitated its interaction with the E3 ubiquitin ligase c-Cbl. This interaction triggeredproteasomal degradation of FLIPS, which promoted activation of caspase-8 and apoptosis. Our findings identify a previouslyunappreciated signaling pathway needed for Mycobacterium tuberculosis–triggered macrophage cell death.
    Original languageEnglish
    Pages (from-to)918-926
    JournalNature Immunology
    Volume10
    Issue number8
    DOIs
    Publication statusPublished - 2009

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