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The Ubiquitin Ligase XIAP Recruits LUBAC for NOD2 Signaling in Inflammation and Innate Immunity


Damgaard, RB; Nachbur, U; Yabal, M; Wong, WWL; 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
2012-06-29
MOLECULAR CELL
Journal Article
46
6
746-758
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 demonferative 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-kappa B 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.
CELL PRESS
NF-KAPPA-B; LINKED LYMPHOPROLIFERATIVE SYNDROME; CHAIN ASSEMBLY COMPLEX; APOPTOSIS; ACTIVATION; DEFICIENCY; PROTEINS; SHARPIN; DISEASE; CANCER
Molecular Genetics of Cancer; Cell Signalling and Cell Death
10.1016/j.molce1.2012.04.014
Copyright © 2012 Elsevier Inc. All rights reserved.