TY - JOUR
T1 - A TNF- and c-Cbl-dependent FLIPS-degradation pathway and its function in Mycobacterium tuberculosis-induced macrophage apoptosis
AU - Kundu, Manikuntala
AU - Pathak, Sushil Kumar
AU - Kumawat, Kuldeep
AU - Basu, Sanchita
AU - Chatterjee, Gargi
AU - Pathak, Shresh
AU - Noguchi, Takuya
AU - Takeda, Kohsuke
AU - Ichijo, Hidenori
AU - Thien, Christine B.F.
AU - Langdon, Wallace Y.
AU - Basu, Joyoti
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=67651163398&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=67651163398&partnerID=8YFLogxK
U2 - 10.1038/ni.1754
DO - 10.1038/ni.1754
M3 - Article
C2 - 19597496
AN - SCOPUS:67651163398
SN - 1529-2908
VL - 10
SP - 918
EP - 926
JO - Nature Immunology
JF - Nature Immunology
IS - 8
ER -
