Identification of a new autoinhibitory domain of interferon-beta promoter stimulator-1 (IPS-1) for the tight regulation of oligomerization-driven signal activation
Identification of a new autoinhibitory domain of interferon-beta promoter stimulator-1 (IPS-1) for the tight regulation of oligomerization-driven signal activation
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DOI：
10.1016/j.bbrc.2019.07.099
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发表时间：
2019-10-01
影响因子：
3.1
通讯作者：
Yoneyama, Mitsutoshi
中科院分区：
文献类型：
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作者：
Takahasi, Kiyohiro;Onomoto, Koji;Yoneyama, Mitsutoshi
病毒感染后，视黄酸诱导基因-I (RIG-I) 样受体检测病毒外源 RNA，并通过与下游线粒体接头分子干扰素 (IFN)-β 启动子刺激物-1 (IPS-1) 直接相互作用传递抗病毒信号，从而抑制病毒复制。尽管已知 IPS-1 会在线粒体上形成类似朊病毒的寡聚体来激活信号传导，但调节寡聚体形成的机制仍不清楚。在这里，我们在氨基酸 180-349 处鉴定了一个自抑制结构域 (AD)，以抑制静息状态下 IPS-1 的寡聚化并调节下游信号传导的激活。尺寸排阻色谱 (SEC) 分析表明，AD 需要通过分子内相互作用来抑制 IPS-1 的半胱天冬酶募集结构域 (CARD) 的自动寡聚化。烟草蚀刻病毒 (TEV) 蛋白酶裂解 IPS-1 CARD 和 AD 之间的肽键可解除自身抑制，这一观察结果支持了这一点。相反，从 IPS-1 中删除该结构域会增强 IFN 报告基因检测中的信号激活，表明 IPS-1 AD 在 IPS-1 介导的抗病毒信号激活的调节中发挥着关键作用。这些发现揭示了与先天抗病毒免疫的严格调节有关的新型分子相互作用。 (C) 2019 Elsevier Inc. 保留所有权利。
Upon viral infection, retinoic acid-inducible gene-I (RIG-I)-like receptors detect viral foreign RNAs and transmit anti-viral signals via direct interaction with the downstream mitochondrial adaptor molecule, interferon (IFN)-beta promoter stimulator-1 (IPS-1), to inhibit viral replication. Although IPS-1 is known to form prion-like oligomers on mitochondria to activate signaling, the mechanisms that regulate oligomer formation remain unclear. Here, we identified an autoinhibitory domain (AD) at amino acids 180-349 to suppress oligomerization of IPS-1 in a resting state and regulate activation of downstream signaling. Size exclusion chromatography (SEC) analysis demonstrated that AD was required to suppress auto-oligomerization of the caspase recruitment domain (CARD) of IPS-1 via intramolecular interactions. This was supported by the observation that cleavage of a peptide bond between IPS-1 CARD and AD by Tobacco Etch virus (TEV) protease relieved auto-inhibition. Conversely, deletion of this domain from IPS-1 enhanced signal activation in IFN-reporter assays, suggesting that IPS-1 AD played a critical role in the regulation of IPS-1-mediated anti-viral signal activation. These findings revealed novel molecular interactions involved in the tight regulation of innate anti-viral immunity. (C) 2019 Elsevier Inc. All rights reserved.