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

被引：360

作者：

Damgaard, Rune Busk ^{[3
,4
]}

Nachbur, Ueli ^{[5
,6
,7
]}

Yabal, Monica ^{[1
]}

Wong, Wendy Wei-Lynn ^{[5
,6
]}

Fiil, Berthe Katrine ^{[3
]}

Kastirr, Mischa ^{[1
]}

Rieser, Eva ^{[8
]}

Rickard, James Arthur ^{[5
,6
]}

Bankovacki, Aleksandra ^{[5
,6
]}

Peschel, Christian ^{[1
]}

Ruland, Juergen ^{[2
,9
]}

Bekker-Jensen, Simon ^{[3
]}

Mailand, Niels ^{[3
]}

Kaufmann, Thomas ^{[10
]}

Strasser, Andreas ^{[6
,7
]}

Walczak, Henning ^{[8
]}

Silke, John ^{[5
,6
,7
]}

Jost, Philipp J. ^{[1
]}

Gyrd-Hansen, Mads ^{[3
,4
]}

机构：

[1] Tech Univ Munich, Klinikum Rechts Isar, Med Klin 3, D-81675 Munich, Germany

[2] Tech Univ Munich, Klinikum Rechts Isar, Inst Klin Chem & Pathobiochem, D-81675 Munich, Germany

[3] Univ Copenhagen, Novo Nordisk Fdn Ctr Prot Res, Dept Dis Biol, DK-2200 Copenhagen, Denmark

[4] Univ Copenhagen, Biotech Res & Innovat Ctr, DK-2200 Copenhagen, Denmark

[5] La Trobe Univ, Dept Biochem, Bundoora, Vic 3086, Australia

[6] Walter & Eliza Hall Inst Med Res, Melbourne, Vic 3052, Australia

[7] Univ Melbourne, Dept Med Biol, Melbourne, Vic 3010, Australia

[8] Univ London Imperial Coll Sci Technol & Med, Dept Med, Tumor Immunol Unit, London W12 0NN, England

[9] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Lab Signaling Immune Syst, D-85764 Neuherberg, Germany

[10] Univ Bern, Inst Pharmacol, CH-3010 Bern, Switzerland

来源：

MOLECULAR CELL | 2012年 / 46卷 / 06期

基金：

瑞士国家科学基金会; 澳大利亚国家健康与医学研究理事会;

关键词：

NF-KAPPA-B; DEFICIENCY; APOPTOSIS; PROTEINS; SHARPIN; POLYUBIQUITINATION; DYSREGULATION; ACTIVATION; INHIBITOR; INFECTION;

D O I：

10.1016/j.molcel.2012.04.014

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：746 / 758

页数：13

共 42 条

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