Disease-causing mutations in the XIAP BIR2 domain impair NOD2-dependent immune signalling.
Disease-causing mutations in the XIAP BIR2 domain impair NOD2-dependent immune signalling.
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DOI：
10.1002/emmm.201303090
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发表时间：
2013-08
影响因子：
11.1
通讯作者：
Gyrd-Hansen, Mads
中科院分区：
文献类型：
--
作者：
Damgaard, Rune Busk;Fiil, Berthe Katrine;Speckmann, Carsten;Yabal, Monica;zur Stadt, Udo;Bekker-Jensen, Simon;Jost, Philipp J.;Ehl, Stephan;Mailand, Niels;Gyrd-Hansen, Mads
X-连锁的细胞凋亡抑制因子(XIAP)是一种重要的泛素连接酶，在含有(NOD)-1和-2模式识别受体的核苷酸结合寡聚化结构域下游提供致炎信号。XIAP的突变会导致X连锁淋巴增殖性综合征2型(XLP2)，这是一种免疫缺陷，与潜在的致命的免疫系统失调有关，其病因尚不清楚。在这里，我们发现XIAP杆状病毒IAP重复(BIR)2结构域是XLP2错义突变的热点。我们证明了XLP2-BIR2突变严重损害了XLP2患者原代细胞和重组的XIAP缺陷细胞系中依赖NOD1/2的免疫信号。XLP2-BIR2突变取消了XIAP-RIPK2的相互作用，导致RIPK2泛素化受损，线性泛素链组装复合体(LUBAC)重新聚集到NOD2-复合体中。我们发现XIAP中的RIPK2结合位点与BIR2的IBM结合口袋重叠，并发现二价Smac模拟化合物(SMC)有效地拮抗NOD2下游的XIAP功能以限制信号传导。这些发现表明，对NOD1/2刺激反应的免疫信号受损是XLP2的一个普遍缺陷，并表明XIAP BIR2-RIPK2相互作用可能是调节炎症信号的药理学靶点。X连锁淋巴增殖综合征-2型是一种由XIAP基因突变引起的免疫缺陷疾病。患者中BIR2结构域的突变损害了RIPK2结合和NOD2依赖的先天免疫信号，解释了一些病理现象。
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. The X-linked lymphoproliferative syndrome type-2 is an immunodeficiency disease caused by mutations in the XIAP gene. BIR2 domain mutations in patients impair RIPK2 binding and NOD2-dependent innate immune signaling, explaining some of the pathology.
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DOI：
10.1084/jem.20091683
发表时间：
2009-08-31
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Casanova JL;Abel L
通讯作者：
Abel L
影响因子：
32.4
作者：
Bertrand, Mathieu J. M.;Doiron, Karine;Saleh, Maya
通讯作者：
Saleh, Maya
影响因子：
64.8
作者：
Liu, ZH;Sun, CH;Fesik, SW
通讯作者：
Fesik, SW
影响因子：
16
作者：
Bertrand, Mathieu J. M.;Milutinovic, Snezana;Barker, Philip A.
通讯作者：
Barker, Philip A.
影响因子：
16
作者：
Damgaard, Rune Busk;Nachbur, Ueli;Gyrd-Hansen, Mads
通讯作者：
Gyrd-Hansen, Mads