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

Manikuntala Kundu1, Sushil Kumar Pathak, Kuldeep Kumawat

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

Nature Immunology
|July 15, 2009
PubMed

Insights

Mycobacterium tuberculosis infection triggers macrophage apoptosis via a novel signaling pathway. Tumor necrosis factor (TNF) activates kinases, leading to FLIP(S) degradation and caspase-8 activation, promoting cell death and limiting bacterial spread.

Area of Science:

  • Cell Biology
  • Immunology
  • Microbiology

Background:

  • Apoptosis is crucial in host-pathogen interactions, particularly between mycobacteria and macrophages.
  • Caspase-8-dependent apoptosis, involving p38 MAP kinase, limits mycobacterial spread.

Purpose of the Study:

  • To elucidate the signaling pathway linking tumor necrosis factor (TNF) release to mycobacteria-induced macrophage apoptosis.
  • To identify key molecular players in Mycobacterium tuberculosis-triggered macrophage cell death.

Main Methods:

  • Investigated the role of TNF in activating signaling cascades.
  • Analyzed the involvement of kinases ASK1, p38, and c-Abl.
  • Examined the phosphorylation and degradation of FLIP(S) and its interaction with c-Cbl.
  • Assessed caspase-8 activation and subsequent apoptosis.

Main Results:

  • TNF activates a pathway involving ASK1, p38, and c-Abl.
  • This pathway leads to FLIP(S) phosphorylation, interaction with c-Cbl, and proteasomal degradation.
  • FLIP(S) degradation promotes caspase-8 activation and macrophage apoptosis.
  • Identified a novel signaling cascade in Mycobacterium tuberculosis-induced apoptosis.

Conclusions:

  • A previously unappreciated signaling pathway mediates Mycobacterium tuberculosis-induced macrophage apoptosis.
  • This pathway involves TNF, ASK1, p38, c-Abl, FLIP(S), c-Cbl, and caspase-8.
  • Understanding this pathway offers insights into host defense mechanisms against mycobacterial infections.

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