BNip3 is a mediator of TNF-induced necrotic cell death.
Tumor necrosis factor (TNF) is a pleiotropic cytokine involved in immune modulation, inflammatory reactions, and target cell death in many pathologic conditions. The cell death pathways triggered by TNF include the caspase-8/Bid-dependent apoptotic pathway and the caspase-independent necrosis pathway (necroptosis). While the signaling pathways activated after binding of TNF to the TNF receptor (TNFR) and subsequent insertion of Bid/Bax/Bik into the outer mitochondrial membrane are relatively well known, other cell death pathways and the participating signaling molecules remain to be clarified. BNip3 is a pro-death protein and a member of the BH3-only Bcl-2 family. When ectopically overexpressed or induced by hypoxia, BNip3 induces various types of cell death via mitochondrial or non-mitochondrial death cascades. In this study using A549 alveolar epithelial cells of the lung, we show that BNip3 is transcriptionally and translationally upregulated by TNF, and its expression level determines the sensitivity to necroptosis induced by TNF. However, BNip3 does not appear to be involved in caspase-8/Bid-dependent apoptotic cell death in these alveolar lung cells. Finally, we show that the generation of reactive oxygen species (ROS) is essential for mitochondrial insertion of BNip3, which is an important step in BNip3-induced mitochondrial catastrophe. Our results indicate that BNip3 is a candidate therapeutic target in pathologic conditions in which TNF causes tissue damage.
Department of Pathology and Medical Science and Engineering Research Center for Bioreaction to Reactive Oxygen Species, School of Medicine, Kyung Hee University, Seoul 130-701, Korea.
Jee-Youn
JY
Kim
Yong-Jun
YJ
Kim
Sun
S
Lee
Jae-Hoon
JH
Park
D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D003720:Densitometry; D004847:Epithelial Cells / Q000378:metabolism; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D005909:Glioblastoma; D006801:Humans; D000860:Hypoxia; D015151:Immunoblotting; D008168:Lung / Q000378:metabolism; D008223:Lymphoma; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D009336:Necrosis; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; C090121:BNIP3 protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D053181:Caspase 8