LGP2 plays a critical role in sensitizing mda-5 to activation by double-stranded RNA.
LGP2 plays a critical role in sensitizing mda-5 to activation by double-stranded RNA.
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DOI：
10.1371/journal.pone.0064202
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Goodbourn S
中科院分区：
文献类型：
--
作者：
Childs KS;Randall RE;Goodbourn S
DExD/H盒RNA解旋酶视黄酸诱导基因-I（RIG-I）和黑素瘤分化相关基因-5（mda-5）在感染细胞的细胞质中有义病毒RNA，并激活触发I型干扰素（IFN）产生的信号转导途径。遗传学和生理学实验室2（LGP 2）被认为是通过调节RIG-I和mda-5的活性来影响IFN的产生，尽管其作用机制尚不清楚，其功能也存在争议。在这里，我们表明，LGP 2的表达增强IFN的诱导聚肌苷酸-聚胞苷酸[聚（I：C）]，通常用作病毒dsRNA的合成模拟物，这是特别显着的诱导剂在有限的水平。所观察到的增强是通过与mda-5的合作介导的，mda-5依赖于LGP 2响应于poly（I：C）的最大活化。这种合作依赖于LGP 2与dsRNA的结合，以及解旋酶结构域IV的存在，这两者都是LGP 2与mda-5相互作用所必需的。相反，虽然RIG-I也可以被poly（I：C）激活，但LGP 2不具有增强RIG-I对IFN诱导的能力，而是作为RIG-I依赖性poly（I：C）信号传导的抑制剂。因此，LGP 2的表达水平是决定细胞对dsRNA诱导的敏感性的关键因素，并且这对于在感染后早期当诱导物水平低时快速激活IFN应答可能是重要的。
The DExD/H box RNA helicases retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation associated gene-5 (mda-5) sense viral RNA in the cytoplasm of infected cells and activate signal transduction pathways that trigger the production of type I interferons (IFNs). Laboratory of genetics and physiology 2 (LGP2) is thought to influence IFN production by regulating the activity of RIG-I and mda-5, although its mechanism of action is not known and its function is controversial. Here we show that expression of LGP2 potentiates IFN induction by polyinosinic-polycytidylic acid [poly(I:C)], commonly used as a synthetic mimic of viral dsRNA, and that this is particularly significant at limited levels of the inducer. The observed enhancement is mediated through co-operation with mda-5, which depends upon LGP2 for maximal activation in response to poly(I:C). This co-operation is dependent upon dsRNA binding by LGP2, and the presence of helicase domain IV, both of which are required for LGP2 to interact with mda-5. In contrast, although RIG-I can also be activated by poly(I:C), LGP2 does not have the ability to enhance IFN induction by RIG-I, and instead acts as an inhibitor of RIG-I-dependent poly(I:C) signaling. Thus the level of LGP2 expression is a critical factor in determining the cellular sensitivity to induction by dsRNA, and this may be important for rapid activation of the IFN response at early times post-infection when the levels of inducer are low.
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