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EMBO Mol Med. 2013 Aug;5(8):1278-95. doi: 10.1002/emmm.201303090. Epub 2013 Jul 1.

Disease-causing mutations in the XIAP BIR2 domain impair NOD2-dependent immune signalling.

Author information

1
Department of Disease Biology, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.

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.

KEYWORDS:

BIR2; NOD2; Smac mimetic compounds; XIAP; XLP2

PMID:
23818254
PMCID:
PMC3944466
DOI:
10.1002/emmm.201303090
[Indexed for MEDLINE]
Free PMC Article
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