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

Damgaard RB., Nachbur U., Yabal M., Wong WW-L., 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.

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.

DOI

10.1016/j.molcel.2012.04.014

Type

Journal article

Journal

Mol Cell

Publication Date

29/06/2012

Volume

46

Pages

746 - 758

Keywords

Animals, Female, Immunity, Innate, Inflammation, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nod2 Signaling Adaptor Protein, Receptor-Interacting Protein Serine-Threonine Kinase 2, Signal Transduction, Ubiquitin, Ubiquitin-Protein Ligases, X-Linked Inhibitor of Apoptosis Protein

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