Journal article
The Ubiquitin Ligase XIAP Recruits LUBAC for NOD2 Signaling in Inflammation and Innate Immunity
RB Damgaard, U Nachbur, M Yabal, WWL Wong, BK Fiil, M Kastirr, E Rieser, JA Rickard, A Bankovacki, C Peschel, J Ruland, S Bekker-Jensen, N Mailand, T Kaufmann, A Strasser, H Walczak, J Silke, PJ Jost, M Gyrd-Hansen
Molecular Cell | CELL PRESS | Published : 2012
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..
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Awarded by Leukemia and Lymphoma Society
Funding Acknowledgements
We thank Drs. H. Steller, R.A. Flavell, M. Kelliher, C. Borner, C.H. Emmerich, P. Meier, O. Gross, C. Duckett, M. Jaattela, P. Schneider, P. Eitz-Ferrer, G. Nunez, B. Vogelstein, and L.A. O'Reilly for gifts of mice, antibodies, and reagents; Dr. M. Frodin for laboratory space (MG.-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 (MG.-H.), the Danish Cancer Society (MG.-H.), a fellowship from the Swiss National Science foundation (# PA00P3_126249 to U.N.), the NHMRC (Canberra, program #461221 and fellowship #461299 to AS.), and the Leukemia and Lymphoma Society (SCOR grant #7413 to AS.). This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS.