Cytosolic virus detection in Caenorhabditis elegans

描述（由申请人提供）：在哺乳动物（包括人）中，RIG-I样RNA解旋酶（RLH）RIG-I、MDA 5和LGP 2检测入侵的病毒RNA，从而启动抗病毒信号级联。有趣的是，虽然共享相似的结构域结构，RIG-I和MDA 5似乎检测不同类别的RNA病毒。LGP 2是另一种类型的RLH，其缺乏RIG-I和MDA 5中保守的N-末端结构域，并且已知在由RIG-I和MDA 5启动的抗病毒信号传导中起调节作用。目前，RIG-I和MDA 5是否识别额外的病毒分子模式以通过RIG-I进行有效的病毒检测，以及什么决定RIG-I和MDA 5的病毒识别特异性在很大程度上仍然未知。由于目前对LGP 2的功能和机制的研究一直存在争议，因此，LGP 2如何调节RIG-I和MDA 5启动的抗病毒信号转导仍不清楚。 我们最近的观察表明，RLH作为一个三成员家族在线虫中的抗病毒RNA沉默中也起着重要作用。最重要的是，其中一个蠕虫RLH，称为DRH-1，似乎有助于病毒检测的方式类似于RIG-I的病毒检测。我们的研究还表明，DRH-3，另一个C。RLH与DRH-1具有相似的结构域结构，在抗病毒RNA沉默中起着独特的作用。第三个C。秀丽线虫RLH，称为DRH-2，缺乏在DRH-1和DRH-3中发现的N-末端结构域，并且已知负调节抗病毒RNA沉默。有趣的是，DRH-2在功能上取代了DRH-1的相应结构域，这表明它可能特异性地调节DRH-1在抗病毒RNA沉默中的功能。综上所述，这些观察结果共同确立了C。elegans是研究RLH介导的病毒感受的理想模型系统。 为了更好地理解如何通过C.通过研究DRH-1的作用以及抗病毒信号如何传递给下游信号分子，阐明DRH-1在病毒感应中的作用机制：（2）通过确定DRH-3在抗病毒沉默和病毒致病中的作用，阐明DRH-1和DRH-3功能特异性的控制机制;（3）确定DRH-2是否特异性靶向并调节DRH-1的功能。预期这些研究的结果还将（1）鉴定RIG-I和MDA 5识别的新分子模式;（2）阐明RIG-I和MDA 5控制病毒识别特异性的机制;（3）对RIG-I和MDA 5启动的LGP 2介导的抗病毒信号转导调节的研究具有直接输入。

DESCRIPTION (provided by applicant): In mammals, including humans, RIG-I-like RNA helicases (RLHs) RIG-I, MDA5 and LGP2 detect invading viral RNAs thereby to initiate an antiviral signaling cascade. Interestingly, although sharing similar domain structure, RIG-I and MDA5 appear to detect RNA viruses of distinct classes. LGP2 is another type of RLH that lacks the N-terminal domains conserved in RIG-I and MDA5 and is known to play a regulatory role in antiviral signaling initiated by RIG-I and MDA5. Currently, whether additional viral molecular patterns are recognized by RIG-I and MDA5 for efficient virus detection by RIG-I and what determines the virus recognition specificity of RIG-I and MDA5 remain largely unknown. Since current studies on the function and mechanism of LGP2 have been generating controversial findings, as a result, how LGP2 regulates the antiviral signaling initiated by RIG-I and MDA5 remains unclear. Our recent observations suggested that RLHs as a three-member family also play important role in antiviral RNA silencing in the nematode Caenorhabditis elegans. Most importantly, one of the worm RLHs, termed DRH-1, appears to contribute to virus detection in a way similar to virus detection by RIG-I. It was also clear from our study that DRH-3, another C. elegans RLH that shares similar domain structure with DRH-1, plays a distinct role in antiviral RNA silencing. The third C. elegans RLH, termed DRH-2, lacks an N-terminal domain found in DRH-1 and DRH-3 and is known to negatively regulate antiviral RNA silencing. Interestingly, DRH-2 functionally replaces the corresponding domains of DRH-1, suggesting that it may specifically regulate the function of DRH-1 in antiviral RNA silencing. Taken together, these observations together establish C. elegans as an ideal model system to study RLH-mediated virus sensing at whole organism level. To better understand how viruses are detected and destroyed by antiviral RNA silencing in C. elegans, here we propose to (1) elucidate the mechanism of DRH-1 in virus sensing by investigating what DRH-1 detects and how the antiviral signal is transmitted to downstream signaling molecules; (2) elucidate the mechanism controlling the function specificity of DRH-1 and DRH-3 by defining a role of DRH-3 in antiviral silencing and viral pathogenesis; (3) determine if DRH-2 specifically targets and regulates the function of DRH-1. Findings from the proposed studies are also expected to (1) identify novel molecular patterns recognized by RIG-I and MDA5; (2) shed light on the mechanism controlling virus recognition specificity of RIG-I and MDA5; (3) have direct input to input to the study of LGP2-mediated regulation of antiviral signaling initiated by RIG-I and MDA5.