TY - JOUR
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
N1 - Funding Information:
We thank Drs. H. Steller, R.A. Flavell, M. Kelliher, C. Borner, C.H. Emmerich, P. Meier, O. Gross, C. Duckett, M. Jäättelä, P. Schneider, P. Eitz-Ferrer, G. Nunez, B. Vogelstein, and L.A. O'Reilly for gifts of mice, antibodies, and reagents; Dr. M. Frödin for laboratory space (M.G.-H. and R.B.D.); Dr. R. Czajko from the Department of Biochemistry at the Royal Melbourne Hospital for measurements of ALT and AST; and Dr. D. Neuberg from the Department of Biostatistics, School of Public Health and Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard for statistical help. We thank Jan Christian for experimental help and Leigh Zawel and Novartis for LBW-242. This work was supported by a Max-Eder Program grant from the Mildred Scheel-Stiftung/Deutsche Krebshilfe (P.J.J.), a Steno Fellowship from the Danish Council for Independent Research - Natural Sciences (M.G.-H.), the Danish Cancer Society (M.G.-H.), a fellowship from the Swiss National Science foundation (# PA00P3_126249 to U.N.), the NHMRC (Canberra, program #461221 and fellowship #461299 to A.S.), and the Leukemia and Lymphoma Society (SCOR grant #7413 to A.S.). This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS.
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.
UR - https://www.scopus.com/pages/publications/84863000898
U2 - 10.1016/j.molcel.2012.04.014
DO - 10.1016/j.molcel.2012.04.014
M3 - Article
C2 - 22607974
AN - SCOPUS:84863000898
SN - 1097-2765
VL - 46
SP - 746
EP - 758
JO - Molecular Cell
JF - Molecular Cell
IS - 6
ER -
SDG 3 Good Health and Well-being