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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Damgaard, RB; Fiil, BK; Speckmann, C; Yabal, M; zur Stadt, U; Bekker-Jensen, S; Jost, PJ; Ehl, S; Mailand, N; Gyrd-Hansen, M.
Disease-causing mutations in the XIAP BIR2 domain impair NOD2-dependent immune signalling.
EMBO Mol Med. 2013; 5(8):1278-1295 Doi: 10.1002/emmm.201303090 [OPEN ACCESS]
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Co-Autor*innen der Med Uni Graz
Jost Philipp

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X-linked Inhibitor of Apoptosis (XIAP) is an essential ubiquitin ligase for pro-inflammatory signalling downstream of the nucleotide-binding oligomerization domain containing (NOD)-1 and -2 pattern recognition receptors. Mutations in XIAP cause X-linked lymphoproliferative syndrome type-2 (XLP2), an immunodeficiency associated with a potentially fatal deregulation of the immune system, whose aetiology is not well understood. Here, we identify the XIAP baculovirus IAP repeat (BIR)2 domain as a hotspot for missense mutations in XLP2. We demonstrate that XLP2-BIR2 mutations severely impair NOD1/2-dependent immune signalling in primary cells from XLP2 patients and in reconstituted XIAP-deficient cell lines. XLP2-BIR2 mutations abolish the XIAP-RIPK2 interaction resulting in impaired ubiquitylation of RIPK2 and recruitment of linear ubiquitin chain assembly complex (LUBAC) to the NOD2-complex. We show that the RIPK2 binding site in XIAP overlaps with the BIR2 IBM-binding pocket and find that a bivalent Smac mimetic compound (SMC) potently antagonises XIAP function downstream of NOD2 to limit signalling. These findings suggest that impaired immune signalling in response to NOD1/2 stimulation is a general defect in XLP2 and demonstrate that the XIAP BIR2-RIPK2 interaction may be targeted pharmacologically to modulate inflammatory signalling. © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.
Find related publications in this database (using NLM MeSH Indexing)
Apoptosis -
Binding Sites -
Cell Line, Tumor -
HEK293 Cells -
Humans -
Inflammation - immunology
Mutation, Missense -
Nod2 Signaling Adaptor Protein - metabolism
Protein Binding -
Protein Structure, Tertiary -
Receptor-Interacting Protein Serine-Threonine Kinase 2 -
Signal Transduction -
Ubiquitin - metabolism
Ubiquitination -
X-Linked Inhibitor of Apoptosis Protein - genetics
X-Linked Inhibitor of Apoptosis Protein - physiology

Find related publications in this database (Keywords)
Smac mimetic compounds
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