Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Damgaard, RB; Nachbur, U; Yabal, M; Wong, WW; Fiil, BK; Kastirr, M; Rieser, E; Rickard, JA; Bankovacki, A; Peschel, C; Ruland, J; Bekker-Jensen, S; Mailand, N; Kaufmann, T; Strasser, A; Walczak, H; Silke, J; Jost, PJ; Gyrd-Hansen, M.
The ubiquitin ligase XIAP recruits LUBAC for NOD2 signaling in inflammation and innate immunity.
Mol Cell. 2012; 46(6):746-758
Doi: 10.1016/j.molcel.2012.04.014
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- Führende Autor*innen der Med Uni Graz
- Jost Philipp
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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. Copyright © 2012 Elsevier Inc. All rights reserved.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Female -
- Immunity, Innate -
- Inflammation - immunology
- Mice -
- Mice, Inbred C57BL -
- Mice, Transgenic -
- Nod2 Signaling Adaptor Protein - genetics
- Nod2 Signaling Adaptor Protein - metabolism
- Receptor-Interacting Protein Serine-Threonine Kinase 2 - genetics
- Receptor-Interacting Protein Serine-Threonine Kinase 2 - metabolism
- Signal Transduction -
- Ubiquitin - metabolism
- Ubiquitin-Protein Ligases - genetics
- Ubiquitin-Protein Ligases - metabolism
- X-Linked Inhibitor of Apoptosis Protein - genetics
- X-Linked Inhibitor of Apoptosis Protein - metabolism