Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
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
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- Co-Autor*innen der Med Uni Graz
- Jost Philipp
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- Abstract:
- 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)
- BIR2
- NOD2
- Smac mimetic compounds
- XIAP
- XLP2