![]() elegans is also regulated by Dicer-related RNA helicase 1 (DRH-1), which is highly homologous to mammalian RIG-I and is largely dispensable for exogenous RNAi ( 15). Worm secondary siRNAs are 22-nt single-stranded RNAs with G as the 5′-terminal nt and antisense to the target mRNA, and are often referred as 22G RNAs ( 23– 25). These include Dicer-1 and dsRNA-binding protein RDE-4(RNA interference-deficient 4), involved in the biogenesis of primary siRNAs predominantly 23 nt in length, and Argonaute protein RDE-1 (RNA interference-deficient 1) and RNA-dependent RNA polymerase RRF-1, required for the production of secondary siRNAs ( 18– 22). elegans requires the genes essential for RNAi induced by exogenous dsRNA ( 12– 17). Genetic studies indicate that antiviral RNAi in C. The nematode Caenorhabditis elegans has recently emerged as a small-animal model for innate immunity studies ( 10, 11). The strong parallel for the antiviral function of RLHs in worms and mammals suggests that detection of viral double-stranded RNA may activate completely unrelated effector mechanisms or, alternatively, that the mammalian RLHs have a conserved activity to stimulate production of viral siRNAs for antiviral immunity by an RNAi effector mechanism. We propose that DRH-1 facilitates the acquisition of viral double-stranded RNA by the worm dicing complex for the subsequent processing into primary siRNAs. However, Northern blot and small RNA deep sequencing analyses indicate that DRH-1 acts to enhance production of viral primary siRNAs, whereas DRH-3 regulates antiviral RNAi by participating in the biogenesis of secondary siRNAs after Dicer-dependent production of primary siRNAs. elegans antiviral RNAi targeting a natural viral pathogen. Genetic analysis revealed an essential role for both DRH-1 and DRH-3 in C. Notably, substitutions in a three-residue motif of the C-terminal regulatory domain of RIG-I that physically interacts with viral double-stranded RNA abolish the antiviral activity of C-terminal regulatory domains of both RIG-I and DRH-1 in C. We also demonstrate that the helicase and C-terminal domains encoded by either worm DRH-2 or human RIG-I can functionally replace the corresponding domains of DRH-1 to mediate antiviral RNAi in C. ![]() Here we show that the antiviral function of DRH-1 requires the RIG-I homologous domains as well as its worm-specific N-terminal domain. RNAi-mediated antiviral immunity in Caenorhabditis elegans requires Dicer-related helicase 1 (DRH-1), which encodes the helicase and C-terminal domains homologous to the mammalian retinoic acid inducible gene I (RIG-I)-like helicase (RLH) family of cytosolic immune receptors.
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