TNF-alpha-induced ROS production triggering apoptosis is directly linked to Romo1 and Bcl-X(L).
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.
Kim
J J
JJ
Korea University College of Medicine, Korea University, Seoul, Republic of Korea.
Lee
S B
SB
Park
J K
JK
Yoo
Y D
YD
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053181:Caspase 8 / Q000378:metabolism; D061945:Caspase Inhibitors; D002460:Cell Line; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D054730:Protein Interaction Domains and Motifs / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D017384:Sequence Deletion / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D053199:TNF Receptor-Associated Death Domain Protein / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*
C494811:BCL2L1 protein, human; D061945:Caspase Inhibitors; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D034741:RNA, Small Interfering; C513338:ROMO1 protein, human; D017382:Reactive Oxygen Species; D053199:TNF Receptor-Associated Death Domain Protein; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D053181:Caspase 8