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

TY - JOUR

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 - zur Stadt, Udo

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 - 2013/8/1

Y1 - 2013/8/1

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.

KW - Apoptosis

KW - Binding Sites

KW - Cell Line, Tumor

KW - HEK293 Cells

KW - Humans

KW - Inflammation

KW - Mutation, Missense

KW - Nod2 Signaling Adaptor Protein

KW - Protein Binding

KW - Protein Structure, Tertiary

KW - Receptor-Interacting Protein Serine-Threonine Kinase 2

KW - Signal Transduction

KW - Ubiquitin

KW - Ubiquitination

KW - X-Linked Inhibitor of Apoptosis Protein

U2 - 10.1002/emmm.201303090

DO - 10.1002/emmm.201303090

M3 - SCORING: Journal article

C2 - 23818254

VL - 5

SP - 1278

EP - 1295

JO - EMBO MOL MED

JF - EMBO MOL MED

SN - 1757-4676

IS - 8

ER -