<br>先天免疫受体RIG-I识别和激活RNA的结构基础,Nature

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先天免疫受体RIG-I识别和激活RNA的结构基础
Nature ( IF 50.5 ) Pub Date : 2011-09-25 , DOI: 10.1038/nature10537
Fuguo Jiang ₁ , Anand Ramanathan , Matthew T Miller , Guo-Qing Tang , Michael Gale , Smita S Patel , Joseph Marcotrigiano

Affiliation

视黄酸诱导基因-I (RIG-I；也称为 DDX58) 是一种细胞质病原体识别受体，可识别病原体相关分子模式 (PAMP) 基序以区分病毒和细胞 RNA。 RIG-I 可由带有或不带有 5'-三磷酸 (ppp) 的平端双链 (ds)RNA、由 5'-ppp 标记的单链 RNA 和多聚尿苷序列激活。与此类 PAMP 基序结合后，RIG-I 启动信号级联，诱导先天免疫防御和炎症细胞因子以建立抗病毒状态。 RIG-I 通路受到高度调控，异常信号传导会导致细胞凋亡、细胞分化改变、炎症、自身免疫性疾病和癌症。 RIG-I 的解旋酶和阻遏结构域 (RD) 识别 dsRNA 和 5'-ppp RNA，以激活两个氨基末端 caspase 募集结构域 (CARD) 进行信号传导。在这里，为了了解解旋酶和 RD 之间对 RNA 结合的协同作用，以及 ATP 水解对 RIG-I 激活的贡献，我们确定了与 dsRNA 和 ATP 类似物复合的人 RIG-I 解旋酶-RD 的结构。解旋酶-RD 在 dsRNA 周围组织成一个环，封住一端，同时使用先前未表征的基序接触两条链以识别 dsRNA。小角度 X 射线散射、有限的蛋白水解和差示扫描荧光测定表明，RIG-I 处于延伸且灵活的构象，在结合 RNA 时会压缩。这些结果提供了解旋酶在 dsRNA 识别中的作用、RD 和解旋酶之间对 RNA 结合的协同作用以及与 dsRNA 结合的全长 RIG-I 的组织的详细视图，并提供了 RNA 结合时构象变化的证据。 RIG-I解旋酶-RD结构与dsRNA易位一致，没有解旋和与RNA的协同结合。该结构对先天免疫产生了前所未有的洞察力，并对生物学的其他领域产生了更广泛的影响，包括利用 DICER 和 FANCM 内同源解旋酶结构域的 RNA 干扰和 DNA 修复。

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Structural basis of RNA recognition and activation by innate immune receptor RIG-I

Retinoic-acid-inducible gene-I (RIG-I; also known as DDX58) is a cytoplasmic pathogen recognition receptor that recognizes pathogen-associated molecular pattern (PAMP) motifs to differentiate between viral and cellular RNAs. RIG-I is activated by blunt-ended double-stranded (ds)RNA with or without a 5′-triphosphate (ppp), by single-stranded RNA marked by a 5′-ppp and by polyuridine sequences. Upon binding to such PAMP motifs, RIG-I initiates a signalling cascade that induces innate immune defences and inflammatory cytokines to establish an antiviral state. The RIG-I pathway is highly regulated and aberrant signalling leads to apoptosis, altered cell differentiation, inflammation, autoimmune diseases and cancer. The helicase and repressor domains (RD) of RIG-I recognize dsRNA and 5′-ppp RNA to activate the two amino-terminal caspase recruitment domains (CARDs) for signalling. Here, to understand the synergy between the helicase and the RD for RNA binding, and the contribution of ATP hydrolysis to RIG-I activation, we determined the structure of human RIG-I helicase-RD in complex with dsRNA and an ATP analogue. The helicase-RD organizes into a ring around dsRNA, capping one end, while contacting both strands using previously uncharacterized motifs to recognize dsRNA. Small-angle X-ray scattering, limited proteolysis and differential scanning fluorimetry indicate that RIG-I is in an extended and flexible conformation that compacts upon binding RNA. These results provide a detailed view of the role of helicase in dsRNA recognition, the synergy between the RD and the helicase for RNA binding and the organization of full-length RIG-I bound to dsRNA, and provide evidence of a conformational change upon RNA binding. The RIG-I helicase-RD structure is consistent with dsRNA translocation without unwinding and cooperative binding to RNA. The structure yields unprecedented insight into innate immunity and has a broader impact on other areas of biology, including RNA interference and DNA repair, which utilize homologous helicase domains within DICER and FANCM.

更新日期：2011-09-25

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