Publications (68) View all
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Article: Linear ubiquitination: a newly discovered regulator of cell signalling.
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ABSTRACT: Ubiquitination is a post-translational modification that creates versatility in cell signalling, in part because eight biochemically different inter-ubiquitin linkages can be formed through the seven internal lysine residues of ubiquitin or its amino-terminal methionine. The latter, referred to as linear or M1 linkage, is created by the linear ubiquitin chain assembly complex (LUBAC). Previously, K63 linkages were thought to be exclusively responsible for ubiquitin-mediated nondegradative functions. It now emerges, however, that M1 ubiquitination is crucial in various pathways, and that generation of a physiological signalling output requires cooperation between different ubiquitin linkage types. Here, we review the currently known functions of LUBAC and M1 ubiquitination, discuss promising future research directions into their functions, and how this may reveal novel therapeutic opportunities for diseases with perturbed linear ubiquitination.Trends in Biochemical Sciences 01/2013; · 10.85 Impact Factor -
Article: The ubiquitin ligase XIAP recruits LUBAC for NOD2 signaling in inflammation and innate immunity.
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ABSTRACT: Nucleotide-binding and oligomerization domain (NOD)-like receptors constitute a first line of defense against invading bacteria. X-linked Inhibitor of Apoptosis (XIAP) is implicated in the control of bacterial infections, and mutations in XIAP are causally linked to immunodeficiency in X-linked lymphoproliferative syndrome type-2 (XLP-2). Here, we demonstrate that the RING domain of XIAP is essential for NOD2 signaling and that XIAP contributes to exacerbation of inflammation-induced hepatitis in experimental mice. We find that XIAP ubiquitylates RIPK2 and recruits the linear ubiquitin chain assembly complex (LUBAC) to NOD2. We further show that LUBAC activity is required for efficient NF-κB activation and secretion of proinflammatory cytokines after NOD2 stimulation. Remarkably, XLP-2-derived XIAP variants have impaired ubiquitin ligase activity, fail to ubiquitylate RIPK2, and cannot facilitate NOD2 signaling. We conclude that XIAP and LUBAC constitute essential ubiquitin ligases in NOD2-mediated inflammatory signaling and propose that deregulation of NOD2 signaling contributes to XLP-2 pathogenesis.Molecular cell 05/2012; 46(6):746-58. · 14.61 Impact Factor -
Article: TRAIL-Rezeptor-Agonisten, eine neue Klasse proapoptotischer Krebstherapeutika
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ABSTRACT: Vor 10 Jahren konnten die Autoren erstmals zeigen, dass der „tumor necrosis factor-related apoptosis-inducing ligand“ (TRAIL) Apoptose spezifisch in Tumorzellen in vivo auslösen kann, ohne normale Zellen zu schädigen. Auf Grundlage dieser Ergebnisse ist die Biologie von TRAIL im zurückliegenden Jahrzehnt Gegenstand intensiver Forschung geworden. Dabei sind teils überraschende Erkenntnisse im Bereich der Signaltransduktion zutage getreten. Die Einbindung dieser aus der Krebsgrundlagenforschung stammenden Ergebnisse wird für die erfolgreiche klinische Entwicklung von TRAIL und agonistischen Antikörpern gegen die beiden apoptosevermittelnden TRAIL-Rezeptoren 1 und 2 von größter Bedeutung sein. In diesem Beitrag werden die Mechanismen TRAIL-induzierter apoptotischer und nichtapoptotischer Signaltransduktion zusammengefasst sowie Resistenzmechanismen und der derzeitige Entwicklungsstand von klinischen Studien, die einen TRAIL-Rezeptor-Agonisten beinhalten, diskutiert. 10 years ago the authors could demonstrate for the first time that the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) causes cell death in tumor cells without harming normal tissue. This finding resulted in the biology of TRAIL becoming the focus of immense research and development efforts during the past decade. The results of this research, at least in some instances, led to surprising insights into the signal transduction processes triggered by TRAIL. The integration of these results from basic cancer research will be crucial for the successful clinical development of TRAIL and antibodies targeting the two apoptosis-inducing TRAIL receptors 1 and 2. This review summarizes the current knowledge of the biochemical mechanisms of TRAIL-induced apoptotic and nonapoptotic signal transduction, and discusses resistance mechanisms und the current development status of the various clinical studies undertaken with the different TRAIL receptor agonists. SchlüsselwörterTRAIL-Apoptose-Todesrezeptor-Krebstherapie Key WordsTRAIL-Apoptosis-Death receptor-Cancer therapyOnkopipeline 04/2012; 3(1):11-23. -
Article: No one can whistle a symphony alone - how different ubiquitin linkages cooperate to orchestrate NF-κB activity.
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ABSTRACT: Although it has been known for a long time that ubiquitylation has a major role in the activation and regulation of the nuclear factor kappa B (NF-κB) pathway, recent studies have revealed that the picture is a lot more complex than originally thought. NF-κB and ubiquitylation initially became linked when it was recognised that lysine (K)48-linked ubiquitin chains are involved in the processing of NF-κB precursors and the degradation of inhibitor of kappa B (IκB) proteins. Soon thereafter, it was reported that K63-linked chains were involved in the assembly of IκB kinase (IKK)-activating complexes and required for activation of the NF-κB signalling pathway. Recently, the discovery that atypical ubiquitin linkages, including linear and K11 linkages, are also involved in the activation of NF-κB has led to the need to re-evaluate existing models of how activation of this transcription factor is initiated and regulated. It is now becoming apparent that not only the canonical types of ubiquitin chains but possibly all linkage types have to be investigated in order to fully comprehend NF-κB activation. This can be considered a turning point in our view of the regulation of one of the most important pathways of gene induction. Hence, in this Commentary, we summarise the information that is currently available and incorporate it into a new model of NF-κB activation, thereby highlighting the emerging new challenges in understanding the role of ubiquitylation in NF-κB activation.Journal of Cell Science 02/2012; 125(Pt 3):549-59. · 6.11 Impact Factor -
Article: TNF and ubiquitin at the crossroads of gene activation, cell death, inflammation, and cancer.
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ABSTRACT: Tumor necrosis factor (TNF) is crucial for innate immunity, but deregulated TNF signaling also plays an eminent role in the pathogenesis of many chronic inflammatory diseases and cancer-related inflammation. The signals that mediate both the beneficial and the harmful effects of TNF are initiated when TNF binds to its receptors on the surface of target cells. TNF receptor 1 (TNFR1) is ubiquitously expressed, whereas TNFR2 is mainly expressed on lymphocytes and endothelial cells. This review focuses on the molecular and physiological consequences of the interaction of TNF with TNFR1. The different outcomes of TNF signaling originate at the apical signaling complex that forms when TNF binds to TNFR1, the TNFR1 signaling complex (TNF-RSC). By integrating recently gained insight on the functional importance of the presence of different types of ubiquitination in the TNF-RSC, including linear ubiquitin linkages generated by the linear ubiquitin chain assembly complex (LUBAC), with the equally recent elucidation of the mode in which ubiquitin-binding domains interact with specific di-ubiquitin linkages, this review develops a new concept for the way the concerted action of different ubiquitination events enables the TNF-RSC to generate its signaling output in a spatio-temporally controlled manner. Finally, it will be explained how these new findings and the emerging concept of differential ubiquitination governing the TNF-RSC may impact future research on the molecular mechanism of TNF signaling and the function of this cytokine in normal physiology, chronic inflammation, and cancer.Immunological Reviews 11/2011; 244(1):9-28. · 11.15 Impact Factor
