- Authors:
-
- Damgaard, Rune Busk ;
- Fiil, Berthe Katrine ;
- Speckmann, Carsten ;
- Yabal, Monica ;
- Stadt, Udo Zur ;
-
Bekker-Jensen, Simon
;
Close
0000-0002-7308-4597
Protein Signaling Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, Københavns Universitet - Jost, Philipp J ;
- Ehl, Stephan ;
- Mailand, Niels ;
- Gyrd-Hansen, Mads
- DOI:
- 10.1002/emmm.201303090
- 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.
- Type:
- Journal article
- Language:
- English
- Published in:
- E M B O Journal, 2013, Vol 5, p. 1278-1295
- Main Research Area:
- Medical science
- Publication Status:
- Published
- Review type:
- Peer Review
- Submission year:
- 2013
- Scientific Level:
- Scientific
- ID:
- 244125796
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