Disease-causing mutations in the XIAP BIR2 domain impair NOD2-dependent immune signalling
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Disease-causing mutations in the XIAP BIR2 domain impair NOD2-dependent immune signalling. / Damgaard, Rune Busk; Fiil, Berthe Katrine; Speckmann, Carsten; Yabal, Monica; Stadt, Udo Zur; Bekker-Jensen, Simon; Jost, Philipp J; Ehl, Stephan; Mailand, Niels; Gyrd-Hansen, Mads.
In: E M B O Journal, Vol. 5, 01.07.2013, p. 1278-1295.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Disease-causing mutations in the XIAP BIR2 domain impair NOD2-dependent immune signalling
AU - Damgaard, Rune Busk
AU - Fiil, Berthe Katrine
AU - Speckmann, Carsten
AU - Yabal, Monica
AU - Stadt, Udo Zur
AU - Bekker-Jensen, Simon
AU - Jost, Philipp J
AU - Ehl, Stephan
AU - Mailand, Niels
AU - Gyrd-Hansen, Mads
N1 - © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.
PY - 2013/7/1
Y1 - 2013/7/1
N2 - 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.
AB - 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.
U2 - 10.1002/emmm.201303090
DO - 10.1002/emmm.201303090
M3 - Journal article
C2 - 23818254
VL - 5
SP - 1278
EP - 1295
JO - E M B O Journal
JF - E M B O Journal
SN - 0261-4189
ER -
ID: 47418158