title: A TNF- and c-Cbl-dependent FLIP(S)-degradation pathway and its function in Mycobacterium tuberculosis-induced macrophage apoptosis.
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 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.
authors: Department of Chemistry, Bose Institute, Kolkata, India.
authors: Manikuntala
authors: M
authors: Kundu
authors: Sushil Kumar
authors: SK
authors: Pathak
authors: Kuldeep
authors: K
authors: Kumawat
authors: Sanchita
authors: S
authors: Basu
authors: Gargi
authors: G
authors: Chatterjee
authors: Shresh
authors: S
authors: Pathak
authors: Takuya
authors: T
authors: Noguchi
authors: Kohsuke
authors: K
authors: Takeda
authors: Hidenori
authors: H
authors: Ichijo
authors: Christine B F
authors: CB
authors: Thien
authors: Wallace Y
authors: WY
authors: Langdon
authors: Joyoti
authors: J
authors: Basu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D006801:Humans; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000382:microbiology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000502:physiology*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D054875:Ubiquitination; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D014409:Tumor Necrosis Factor-alpha; D050721:Proto-Oncogene Proteins c-cbl; D016315:Proto-Oncogene Proteins c-abl; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; D053181:Caspase 8; D046988:Proteasome Endopeptidase Complex; C067419:CBL protein, human; C493849:Cbl protein, mouse