title: The 55-kDa tumor necrosis factor receptor induces clustering of mitochondria through its membrane-proximal region.
abstract: The cytokine tumor necrosis factor (TNF) activates diverse signaling molecules resulting in gene expression, differentiation, and/or cell death. Here we report a novel feature induced by TNF, namely translocation of mitochondria from a dispersed distribution to a perinuclear cluster. Mitochondrial translocation correlated with sensitivity to the cell death-inducing activity of TNF and was mediated by the 55-kDa TNF receptor (TNF-R55), but not by Fas, indicating that the signaling pathway requires a TNF-R55-specific but death domain-independent signal. Indeed, using L929 cells that express mutant TNF-R55, we showed that the membrane-proximal region of TNF-R55 was essential for signaling to mitochondrial translocation. In the absence of translocation, the cell death response was markedly delayed, pointing to a cooperative effect on cell death. Translocation of mitochondria, although dependent on the microtubules, was not imposed by the latter and was equally induced by TNF-independent immunoinhibition of the motor protein kinesin. Additionally, immunoinhibition with antibody directed against the tail domain of kinesin synergized with TNF-induced cell death. Based on this functional mimicry, we propose that a TNF-R55 membrane-proximal region-dependent signal impedes mitochondria-associated kinesin, resulting in cooperation with the TNF-R55 death domain-induced cytotoxic response and causing the observed clustering of mitochondria.
authors.affiliation: Department of Molecular Biology, Molecular Immunology Unit, Flanders Interuniversity Institute for Biotechnology and University of Ghent, B-9000 Ghent, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: De Vos
authors.forename: V
authors.initials: V
authors.lastname: Goossens
authors.forename: E
authors.initials: E
authors.lastname: Boone
authors.forename: D
authors.initials: D
authors.lastname: Vercammen
authors.forename: K
authors.initials: K
authors.lastname: Vancompernolle
authors.forename: P
authors.initials: P
authors.lastname: Vandenabeele
authors.forename: G
authors.initials: G
authors.lastname: Haegeman
authors.forename: W
authors.initials: W
authors.lastname: Fiers
authors.forename: J
authors.initials: J
authors.lastname: Grooten
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000096:biosynthesis / Q000502:physiology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007739:L Cells; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D009068:Movement; D016328:NF-kappa B / Q000378:metabolism; D017382:Reactive Oxygen Species; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000494:pharmacology; D015398:Signal Transduction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D019014:fas Receptor / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor