A comprehensive interaction study provides a potential domain interaction network of human death domain superfamily proteins.
A comprehensive interaction study provides a potential domain interaction network of human death domain superfamily proteins.
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DOI：
10.1038/s41418-021-00796-x
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发表时间：
2021-11
影响因子：
12.4
通讯作者：
Masumoto J
中科院分区：
文献类型：
--
作者：
Zhou W;Kaneko N;Nakagita T;Takeda H;Masumoto J
人类死亡结构域超家族蛋白(DDSPs)在许多与细胞死亡和炎症有关的信号通路中发挥着重要作用。由遗传性基因突变引起的这些DDSP相互作用的破坏或结构性激活与免疫缺陷和/或自身炎症性疾病密切相关；然而，在这些疾病的表型诊断中尚未发现负责任的基因突变。在这项研究中，我们全面研究了死亡折叠结构域之间的相互作用，以探索人类DDSP介导的信号网络。我们获得了116个DDSP结构域，并利用放大发光邻近均相分析对13,924个反应进行了域-域相互作用分析。这些数据与之前报道的相互作用基本一致。我们还发现了新的可能的相互作用，包括CARD10的caspase招募结构域(CARD)和NOD2的串联卡-卡结构域之间的相互作用，这一点通过相互免疫共沉淀得到了证实。这项研究能够预测人类DDSP的相互作用网络，阐明致病机制，并将有助于确定治疗免疫缺陷和自身炎症性疾病的药物靶点。
Human death domain superfamily proteins (DDSPs) play important roles in many signaling pathways involved in cell death and inflammation. Disruption or constitutive activation of these DDSP interactions due to inherited gene mutations is closely related to immunodeficiency and/or autoinflammatory diseases; however, responsible gene mutations have not been found in phenotypical diagnosis of these diseases. In this study, we comprehensively investigated the interactions of death-fold domains to explore the signaling network mediated by human DDSPs. We obtained 116 domains of DDSPs and conducted a domain–domain interaction assay of 13,924 reactions in duplicate using amplified luminescent proximity homogeneous assay. The data were mostly consistent with previously reported interactions. We also found new possible interactions, including an interaction between the caspase recruitment domain (CARD) of CARD10 and the tandem CARD–CARD domain of NOD2, which was confirmed by reciprocal co-immunoprecipitation. This study enables prediction of the interaction network of human DDSPs, sheds light on pathogenic mechanisms, and will facilitate identification of drug targets for treatment of immunodeficiency and autoinflammatory diseases.
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