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.
The Caenorhabditis elegans nematode has been serving as a model organism for in-depth study of innate immunity and development in humans. Our recent observations suggested that the innate antiviral mechanisms in C. elegans and humans share key components in virus detection. Here we propose to elucidate the mechanism controlling cytosolic virus detection in C. elegans, aiming to improve our understanding regarding how invading viruses are detected by human innate antiviral mechanisms.