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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 [OPEN ACCESS]
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Jost Philipp

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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

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