title: Novel phosphorylation-dependent ubiquitination of tristetraprolin by mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 1 (MEKK1) and tumor necrosis factor receptor-associated factor 2 (TRAF2).
abstract: Acute versus chronic inflammation is controlled by the accurate activation and regulation of interdependent signaling cascades. TNF-receptor 1 engagement concomitantly activates NF-κB and JNK signaling. The correctly timed activation of these pathways is the key to account for the balance between NF-κB-mediated cell survival and cell death, the latter fostered by prolonged JNK activation. Tristetraprolin (TTP), initially described as an mRNA destabilizing protein, acts as negative feedback regulator of the inflammatory response: it destabilizes cytokine-mRNAs but also acts as an NF-κB inhibitor by interfering with the p65/RelA nuclear import pathway. Our biochemical studies provide evidence that TTP contributes to the NF-κB/JNK balance. We find that the MAP 3-kinase MEKK1 acts as a novel TTP kinase that, together with the TNF receptor-associated factor 2 (TRAF2), constitutes not only a main determinate of the NF-κB-JNK cross-talk but also facilitates "TTP hypermodification": MEKK1 triggers TTP phosphorylation as prerequisite for its Lys-63-linked, TRAF2-mediated ubiquitination. Consequently, TTP no longer affects NF-κB activity but promotes the activation of JNK. Based on our data, we suggest a model where upon TNFα induction, TTP transits a hypo- to hypermodified state, thereby contributing to the molecular regulation of NF-κB versus JNK signaling cascades.
authors.affiliation: Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Lazarettgasse 19, 1090 Vienna, Austria. Electronic address: yvonne.schichl@gmx.net.
authors.forename: Yvonne M
authors.initials: YM
authors.lastname: Schichl
authors.affiliation: Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Lazarettgasse 19, 1090 Vienna, Austria.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Resch
authors.affiliation: Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Lazarettgasse 19, 1090 Vienna, Austria.
authors.forename: Christof E
authors.initials: CE
authors.lastname: Lemberger
authors.affiliation: Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Lazarettgasse 19, 1090 Vienna, Austria.
authors.forename: Dominik
authors.initials: D
authors.lastname: Stichlberger
authors.affiliation: Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Lazarettgasse 19, 1090 Vienna, Austria.
authors.forename: Rainer
authors.initials: R
authors.lastname: de Martin
mesh_terms: D000256:Adenoviridae / Q000378:metabolism; D002470:Cell Survival; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007249:Inflammation; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000737:chemistry; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism*; D051816:Tristetraprolin / Q000737:chemistry*; D025801:Ubiquitin / Q000737:chemistry*
chemical_list: D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; D047992:TNF Receptor-Associated Factor 2; D051816:Tristetraprolin; D025801:Ubiquitin; D051550:I-kappa B Kinase; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human