Cytosolic virus detection in Caenorhabditis elegans

秀丽隐杆线虫胞浆病毒检测

基本信息

批准号：
8824358
负责人：
Rui Lu
金额：
$ 23.02万
依托单位：
LOUISIANA STATE UNIV A&M COL BATON ROUGE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-16 至 2016-03-31
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：在包括人类的哺乳动物中，RIG-I样RNA解旋酶（RLHS）RIG-I，MDA5和LGP2检测入侵的病毒RNA，从而启动抗病毒信号传导级联。有趣的是，尽管共享相似的域结构，但RIG-I和MDA5似乎检测了不同类别的RNA病毒。 LGP2是另一种缺乏RIG-I和MDA5中N末端结构域的RLH，众所周知，它在RIG-I和MDA5发起的抗病毒信号中起着调节作用。目前，RIG-I和MDA5是否识别出其他病毒分子模式，以通过RIG-1的有效病毒检测以及确定RIG-I和MDA5病毒识别特异性的有效病毒检测。由于目前对LGP2功能和机制的研究一直在产生有争议的发现，因此，LGP2如何调节RIG-I和MDA5引起的抗病毒信号传导尚不清楚。我们最近的观察结果表明，RLHS作为一个三成员的家族在线虫秀丽隐杆线虫中的抗病毒RNA沉默中也起着重要作用。最重要的是，称为DRH-1的蠕虫RLH中的一种似乎以类似于RIG-I检测的病毒检测的方式导致病毒检测。从我们的研究中也可以清楚地看出，与DRH-1共享类似域结构的另一位C.秀韧带RLH DRH-3在抗病毒RNA沉默中起着独特的作用。第三枚秀丽隐杆线虫RLH称为DRH-2，缺少在DRH-1和DRH-3中发现的N末端结构域，并且已知会对抗病毒RNA沉默进行负调节。有趣的是，DRH-2在功能上替代了DRH-1的相应域，这表明它可以特别调节DRH-1在抗病毒RNA沉默中的功能。综上所述，这些观察结果共同建立了秀丽隐杆线虫作为一个理想的模型系统，可以研究RLH介导的整个生物水平的病毒感测。为了更好地了解秀丽隐杆线虫中抗病毒RNA沉默如何检测和破坏病毒，我们在这里提议（1）通过研究DRH-1检测到什么以及如何将抗病毒信号传递到下游信号分子，以阐明病毒传感中DRH-1的机制；（2）通过定义DRH-3在抗病毒沉默和病毒发病机理中的作用来阐明控制DRH-1和DRH-3功能特异性的机制；（3）确定DRH-2是否特异性靶向并调节DRH-1的功能。拟议研究的结果还有望（1）确定由RIG-I和MDA5识别的新型分子模式；（2）阐明了控制RIG-I和MDA5病毒识别特异性的机制；（3）直接输入输入了RIG-I和MDA5引发的LGP2介导的抗病毒信号的调节。