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RNAi-mediated antièiral 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. Here we show that the antièiral function of DRH-1 requires the RIG-I homologous domains as well as its wormspecific N-terminal domain. 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 antièiral RNAi in C. elegans. Notably, substitutions in a three-residue motif of the C-terminal regulatory domain of RIG-I that physically interacts with èiral double-stranded RNA abolish the antièiral actièity of C-terminal regulatory domains of both RIG-I and DRH-1 in C. elegans. Genetic analysis reèealed an essential role for both DRH-1 and DRH-3 in C. elegans antièiral RNAi targeting a natural èiral pathogen. Howeèer, Northern blot and small RNA deep sequencing analyses indicate that DRH-1 acts to enhance production of èiral primary siRNAs, whereas DRH-3 regulates antièiral RNAi by participating in the biogenesis of secondary siRNAs after Dicer-dependent production of primary siRNAs. We propose that DRH-1 facilitates the acquisition of èiral double-stranded RNA by the worm dicing complex for the subsequent processing into primary siRNAs. The strong parallel for the antièiral function of RLHs in worms and mammals suggests that detection of èiral doublestranded RNA may actièate completely unrelated effector mechanisms or, alternatièely, that the mammalian RLHs haèe a conserèed actièity to stimulate production of èiral siRNAs for antièiral immunity by an RNAi effector mechanism.

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Proceedings of the National Academy of Sciences of the United States of America

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