title: The ubiquitin ligase XIAP recruits LUBAC for NOD2 signaling in inflammation and innate immunity.
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.
authors.affiliation: Department of Disease Biology, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Rune Busk
authors.initials: RB
authors.lastname: Damgaard
authors.forename: Ueli
authors.initials: U
authors.lastname: Nachbur
authors.forename: Monica
authors.initials: M
authors.lastname: Yabal
authors.forename: Wendy Wei-Lynn
authors.initials: WW
authors.lastname: Wong
authors.forename: Berthe Katrine
authors.initials: BK
authors.lastname: Fiil
authors.forename: Mischa
authors.initials: M
authors.lastname: Kastirr
authors.forename: Eva
authors.initials: E
authors.lastname: Rieser
authors.forename: James Arthur
authors.initials: JA
authors.lastname: Rickard
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Bankovacki
authors.forename: Christian
authors.initials: C
authors.lastname: Peschel
authors.forename: Juergen
authors.initials: J
authors.lastname: Ruland
authors.forename: Simon
authors.initials: S
authors.lastname: Bekker-Jensen
authors.forename: Niels
authors.initials: N
authors.lastname: Mailand
authors.forename: Thomas
authors.initials: T
authors.lastname: Kaufmann
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
authors.forename: Henning
authors.initials: H
authors.lastname: Walczak
authors.forename: John
authors.initials: J
authors.lastname: Silke
authors.forename: Philipp J
authors.initials: PJ
authors.lastname: Jost
authors.forename: Mads
authors.initials: M
authors.lastname: Gyrd-Hansen
mesh_terms: D000818:Animals; D005260:Female; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D025801:Ubiquitin; D051636:X-Linked Inhibitor of Apoptosis Protein; D044767:Ubiquitin-Protein Ligases; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2