title: Polyubiquitinated tristetraprolin protects from TNF-induced, caspase-mediated apoptosis.
abstract: Binding of TNF to its receptor (TNFR1) elicits the spatiotemporal assembly of two signaling complexes that coordinate the balance between cell survival and cell death. We have shown previously that, following TNF treatment, the mRNA decay protein tristetraprolin (TTP) is Lys-63-polyubiquitinated by TNF receptor-associated factor 2 (TRAF2), suggesting a regulatory role in TNFR signaling. Here we demonstrate that TTP interacts with TNFR1 in a TRAF2-dependent manner, thereby initiating the MEKK1/MKK4-dependent activation of JNK activities. This regulatory function toward JNK activation but not NF-κB activation depends on lysine 105 of TTP, which we identified as the corresponding TRAF2 ubiquitination site. Disabling TTP polyubiquitination results in enhanced TNF-induced apoptosis in cervical cancer cells. Together, we uncover a novel aspect of TNFR1 signaling where TTP, in alliance with TRAF2, acts as a balancer of JNK-mediated cell survival versus death.
authors: From the Department of Vascular Biology and Thrombosis Research, Medical University of Vienna, Schwarzspanierstraße 17, 1090 Vienna, Austria.
authors: Ulrike
authors: U
authors: Resch
authors: From the Department of Vascular Biology and Thrombosis Research, Medical University of Vienna, Schwarzspanierstraße 17, 1090 Vienna, Austria.
authors: Angélica
authors: A
authors: Cuapio
authors: From the Department of Vascular Biology and Thrombosis Research, Medical University of Vienna, Schwarzspanierstraße 17, 1090 Vienna, Austria.
authors: Caterina
authors: C
authors: Sturtzel
authors: From the Department of Vascular Biology and Thrombosis Research, Medical University of Vienna, Schwarzspanierstraße 17, 1090 Vienna, Austria.
authors: Erhard
authors: E
authors: Hofer
authors: From the Department of Vascular Biology and Thrombosis Research, Medical University of Vienna, Schwarzspanierstraße 17, 1090 Vienna, Austria.
authors: Rainer
authors: R
authors: de Martin
authors: From the Department of Vascular Biology and Thrombosis Research, Medical University of Vienna, Schwarzspanierstraße 17, 1090 Vienna, Austria yvonne.holper-schichl@meduniwien.ac.at yvonne.schichl@gmx.net.
authors: Yvonne M
authors: YM
authors: Holper-Schichl
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism; D018345:Mice, Knockout; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D025821:Polyubiquitin / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism; D051816:Tristetraprolin / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; D047992:TNF Receptor-Associated Factor 2; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha; D025821:Polyubiquitin; D048031:JNK Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human; D020169:Caspases; D008239:Lysine
keywords: Apoptosis; Cell Proliferation; NF-κB; Tristetraprolin; Tumor Necrosis Factor (TNF); c-Jun N-terminal Kinase (JNK)