The ubiquitin ligase XIAP recruits LUBAC for NOD2 signaling in inflammation and innate immunity

Damgaard, Rune Busk; Nachbur, Ueli; Yabal, Monica; Wong, Wendy Wei-Lynn; Fiil, Berthe Katrine; Kastirr, Mischa; Rieser, Eva; Rickard, James Arthur; Bankovacki, Aleksandra; Peschel, Christian; Ruland, Juergen; Bekker-Jensen, Simon; Mailand, Niels; Kaufmann, Thomas; Strasser, Andreas; Walczak, Henning; Silke, John; Jost, Philipp J; Gyrd-Hansen, Mads (2012). The ubiquitin ligase XIAP recruits LUBAC for NOD2 signaling in inflammation and innate immunity. Molecular cell, 46(6), pp. 746-58. Cambridge, Mass.: Cell Press 10.1016/j.molce1.2012.04.014

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology

UniBE Contributor:

Kaufmann, Thomas

ISSN:

1097-2765

Publisher:

Cell Press

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:35

Last Modified:

07 Dec 2013 13:16

Publisher DOI:

10.1016/j.molce1.2012.04.014

PubMed ID:

22607974

Web of Science ID:

000306097000006

URI:

https://boris.unibe.ch/id/eprint/14089 (FactScience: 220896)

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