The Ubiquitin Ligase XIAP Recruits LUBAC for NOD2 Signaling in Inflammation and Innate Immunity
| Autor: | Henning Walczak, Ueli Nachbur, James A Rickard, Monica Yabal, Mischa Kastirr, W. Wei-Lynn Wong, Niels Mailand, Simon Bekker-Jensen, Juergen Ruland, Christian Peschel, Philipp J. Jost, Andreas Strasser, John Silke, Thomas Kaufmann, Rune Busk Damgaard, Eva Rieser, Berthe Katrine Fiil, Aleksandra Bankovacki, Mads Gyrd-Hansen |
|---|---|
| Přispěvatelé: | University of Zurich, Jost, P J |
| Rok vydání: | 2012 |
| Předmět: |
Ubiquitin-Protein Ligases
Nod2 Signaling Adaptor Protein Mice Transgenic X-Linked Inhibitor of Apoptosis Protein 610 Medicine & health 10263 Institute of Experimental Immunology Inhibitor of apoptosis Proinflammatory cytokine 1307 Cell Biology RIPK2 Mice 03 medical and health sciences 0302 clinical medicine Ubiquitin Receptor-Interacting Protein Serine-Threonine Kinase 2 1312 Molecular Biology Animals XIAP Deficiency Molecular Biology 030304 developmental biology Inflammation 0303 health sciences biology Cell Biology Immunity Innate digestive system diseases 3. Good health XIAP Ubiquitin ligase Mice Inbred C57BL 030220 oncology & carcinogenesis biology.protein Cancer research 570 Life sciences Female Signal transduction Signal Transduction |
| Zdroj: | Molecular cell Mol. Cell 46, 746-758 (2012) |
| ISSN: | 1097-2765 |
| DOI: | 10.1016/j.molcel.2012.04.014 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|