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

Rune Busk Damgaard; Ueli Nachbur; Monica Yabal; Wendy Wei-Lynn Wong; Berthe Katrine Fiil; Mischa Kastirr; Eva Rieser; James Arthur Rickard; Aleksandra Bankovacki; Christian Peschel; Juergen Ruland; Simon Bekker-Jensen; Niels Mailand; Thomas Kaufmann; Andreas Strasser; Henning Walczak; John Silke; Philipp J Jost; Mads Gyrd-Hansen

doi:10.1016/j.molcel.2012.04.014

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

Rune Busk Damgaard, Ueli Nachbur, Monica Yabal, Wendy Wei-Lynn Wong, Berthe Katrine Fiil, Mischa Kastirr, Eva Rieser, James Arthur Rickard, Aleksandra Bankovacki, Christian Peschel, Juergen Ruland, Simon Bekker-Jensen, Niels Mailand, Thomas Kaufmann, Andreas Strasser, Henning Walczak, John Silke, Philipp J Jost, Mads Gyrd-Hansen

242 Citations (Scopus)

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.

Original language	English
Journal	Molecular Cell
Volume	46
Issue number	6
Pages (from-to)	746-58
Number of pages	13
ISSN	1097-4164
DOIs	https://doi.org/10.1016/j.molcel.2012.04.014
Publication status	Published - 29 Jun 2012

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Damgaard, R. B., Nachbur, U., Yabal, M., Wong, W. W.-L., Fiil, B. K., Kastirr, M., Rieser, E., Rickard, J. A., Bankovacki, A., Peschel, C., Ruland, J., Bekker-Jensen, S., Mailand, N., Kaufmann, T., Strasser, A., Walczak, H., Silke, J., Jost, P. J., & Gyrd-Hansen, M. (2012). The Ubiquitin Ligase XIAP Recruits LUBAC for NOD2 Signaling in Inflammation and Innate Immunity. Molecular Cell, 46(6), 746-58. https://doi.org/10.1016/j.molcel.2012.04.014

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 2012, 'The Ubiquitin Ligase XIAP Recruits LUBAC for NOD2 Signaling in Inflammation and Innate Immunity', Molecular Cell, vol. 46, no. 6, pp. 746-58. https://doi.org/10.1016/j.molcel.2012.04.014

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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.",

author = "Damgaard, {Rune Busk} and Ueli Nachbur and Monica Yabal and Wong, {Wendy Wei-Lynn} and Fiil, {Berthe Katrine} and Mischa Kastirr and Eva Rieser and Rickard, {James Arthur} and Aleksandra Bankovacki and Christian Peschel and Juergen Ruland and Simon Bekker-Jensen and Niels Mailand and Thomas Kaufmann and Andreas Strasser and Henning Walczak and John Silke and Jost, {Philipp J} and Mads Gyrd-Hansen",

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T1 - The Ubiquitin Ligase XIAP Recruits LUBAC for NOD2 Signaling in Inflammation and Innate Immunity

AU - Damgaard, Rune Busk

AU - Nachbur, Ueli

AU - Yabal, Monica

AU - Wong, Wendy Wei-Lynn

AU - Fiil, Berthe Katrine

AU - Kastirr, Mischa

AU - Rieser, Eva

AU - Rickard, James Arthur

AU - Bankovacki, Aleksandra

AU - Peschel, Christian

AU - Ruland, Juergen

AU - Bekker-Jensen, Simon

AU - Mailand, Niels

AU - Kaufmann, Thomas

AU - Strasser, Andreas

AU - Walczak, Henning

AU - Silke, John

AU - Jost, Philipp J

AU - Gyrd-Hansen, Mads

PY - 2012/6/29

Y1 - 2012/6/29

N2 - 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.

AB - 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.

U2 - 10.1016/j.molcel.2012.04.014

DO - 10.1016/j.molcel.2012.04.014

M3 - Journal article

C2 - 22607974

SN - 1097-4164

VL - 46

SP - 746

EP - 758

JO - Molecular Cell

JF - Molecular Cell

IS - 6

ER -

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

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