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

Rune Busk Damgaard, Berthe Katrine Fiil, Carsten Speckmann, Monica Yabal, Udo Zur Stadt, Simon Bekker-Jensen, Philipp J Jost, Stephan Ehl, Niels Mailand, Mads Gyrd-Hansen

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130 Citations (Scopus)

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.
Original languageEnglish
JournalE M B O Journal
Volume5
Pages (from-to)1278-1295
Number of pages18
ISSN0261-4189
DOIs
Publication statusPublished - 1 Jul 2013

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