Abstract
Reactive oxygen species (ROS) produced by tumor necrosis factor-alpha (TNF-alpha) have an important function in cell death by activating c-Jun N-terminal kinase. However, the exact mechanism of mitochondrial ROS production, after TNF-alpha stimulation, is not clearly understood. In this study, we determined that ROS modulator 1 (Romo1) and B-cell lymphoma-extra large (Bcl-X(L)) are directly associated with TNF-alpha-induced ROS production. In response to TNF-alpha, TNF complex II, which consists of receptor-interacting protein 1, TNF receptor-associated protein with death domain, TNF receptor-associated factor 2, Fas-associated death domain protein, and pro-caspase-8, binds to the C-terminus of Romo1 located in the mitochondria. Concurrently, Romo1 recruits Bcl-X(L) to reduce the mitochondrial membrane potential, resulting in ROS production and apoptotic cell death. On the basis of these results, we suggest that Romo1 is a molecular bridge between TNF-alpha signaling and the mitochondria for ROS production that triggers TNF-alpha-mediated apoptosis, as well as a novel target in the development of anti-inflammatory agents that block the origin of ROS production.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects
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Apoptosis / physiology*
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Caspase 8 / metabolism
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Caspase Inhibitors
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Cell Line
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Fas-Associated Death Domain Protein / metabolism
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HeLa Cells
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Humans
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JNK Mitogen-Activated Protein Kinases / metabolism
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Membrane Potential, Mitochondrial / drug effects
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Membrane Potential, Mitochondrial / genetics
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mitochondria / drug effects
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Mitochondria / metabolism
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Mitochondrial Proteins / genetics
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Mitochondrial Proteins / metabolism*
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Models, Biological
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / metabolism
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Protein Binding / physiology
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Protein Interaction Domains and Motifs / physiology
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RNA, Small Interfering / genetics
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Reactive Oxygen Species / metabolism*
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Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
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Sequence Deletion / genetics
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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TNF Receptor-Associated Death Domain Protein / metabolism
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TNF Receptor-Associated Factor 2 / metabolism
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Transfection
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Tumor Necrosis Factor-alpha / pharmacology*
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bcl-X Protein / genetics
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bcl-X Protein / metabolism*
Substances
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BCL2L1 protein, human
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Caspase Inhibitors
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FADD protein, human
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Fas-Associated Death Domain Protein
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Membrane Proteins
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Mitochondrial Proteins
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NF-kappa B
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RNA, Small Interfering
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ROMO1 protein, human
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Reactive Oxygen Species
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TNF Receptor-Associated Death Domain Protein
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TNF Receptor-Associated Factor 2
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Tumor Necrosis Factor-alpha
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bcl-X Protein
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Receptor-Interacting Protein Serine-Threonine Kinases
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JNK Mitogen-Activated Protein Kinases
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Caspase 8