Regulation of the Deubiquitinase CYLD in the TNFR signaling pathway

Media type: E-Book; Thesis

Title: Regulation of the Deubiquitinase CYLD in the TNFR signaling pathway

Contributor: Schlicher, Lisa Katharina [Author]; Maurer, Ulrich [Degree supervisor]

Corporation: Albert-Ludwigs-Universität Freiburg, Institut für Molekulare Medizin und Zellforschung ; Albert-Ludwigs-Universität Freiburg, Fakultät für Biologie ; Albert-Ludwigs-Universität Freiburg, Medizinische Fakultät ; Albert-Ludwigs-Universität Freiburg

Published: Freiburg: Universität, 2017

Extent: Online-Ressource

Language: English

DOI: 10.6094/UNIFR/12788

Identifier:

Keywords: Tumor-Nekrose-Faktor ; Immunologie ; Immunsystem ; Lymphozyt ; Leukozyt ; Immunität ; Resistenz ; Immunchemie ; (local)doctoralThesis ; Hochschulschrift

Origination:

University thesis: Dissertation, Albert-Ludwigs-Universität Freiburg, 2017

Footnote: IN COPYRIGHT http://rightsstatements.org/page/InC/1.0 rs

Description: Abstract: Signaling mediated by innate immune and inflammatory cytokine receptors, is essential for an appropriate response of the immune system to invading pathogens. Dysregulations of these pathways cause a variety of autoimmune and chronic inflammatory diseases. The well characterized TNFR (Tumor Necrosis Factor Receptor) pathway is induced by the cytokine TNF, a key regulator of the innate immune response. TNF is able to induce inflammation and cell-survival, but also apoptotic or necroptotic cell death signaling via the very same receptor. K63- and M1-linked ubiquitinations are crucial posttranslational modifications (PTM) for TNF-mediated signaling. These non-degradative ubiquitinations are essential for the assembly of the TNFR signaling complex (TNF-RSC), mediating the activation of pro-survival/ inflammatory NFκB-/MAPK-signaling. Deubiquitinases (DUBs), such as the enzyme CYLD counteract these ubiquitin modifications, ensuring an appropriate signal strength, but also promoting the conversion from a pro-survival signaling towards cell death execution. However, despite its important function, the regulation of CYLD remains incompletely understood. Therefore, the aim of this study was to investigate whether unknown regulatory mechanisms exist, which have an impact on CYLD’s function.<br>In the first part of this study, TAK1 could be identified as a novel kinase able to phosphorylate CYLD in vitro. Seven so far unknown candidate phosphorylation sites of CYLD were identified. However no regulatory impact of these sites in TNF-mediated signaling could be found. In the second part of this study, SPATA2 was identified in a search for novel regulatory interaction partner of CYLD. SPATA2 interacts with CYLD, but also with the LUBAC component HOIP via two distinct domains, acting as a CYLD-HOIP bridging factor. Thereby, SPATA2 is responsible for recruiting CYLD to the TNFR through the LUBAC complex, making SPATA2 a novel member of the TNF-RSC. Moreover, SPATA2 acts as an allosteric activator of CYLD’s catalytic activity. In consequence, SPATA2 substantially attenuates TNF-induced NFκB-/MAPK-signaling. Conversely, SPATA2 is required for TNF-induced apoptosis-, but also necroptosis-induction, as it was shown for CYLD. Thus, this study identifies SPATA2 as a crucial regulator of the DUB CYLD and thus an important factor in the TNF signaling pathway

Access State: Open Access

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