Caenorhabditis elegans Dicer acts with the RIG-I-like helicase DRH-1 and RDE-4 to cleave dsRNA

• Published in: eLife Vol. 13
• Main Authors: Consalvo, Claudia D, Aderounmu, Adedeji M, Donelick, Helen M, Aruscavage, P Joseph, Eckert, Debra M, Shen, Peter S, Bass, Brenda L
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 15-05-2024; eLife Sciences Publications, Ltd
• Subjects: Adenosine Triphosphate - metabolism; Amino acids; Animals; antiviral; Antiviral drugs; autoinhibition; Biochemistry and Chemical Biology; Caenorhabditis elegans; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - chemistry; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Cryoelectron Microscopy; DEAD Box Protein 58 - chemistry; DEAD Box Protein 58 - genetics; DEAD Box Protein 58 - metabolism; DEAD-box RNA Helicases - chemistry; DEAD-box RNA Helicases - genetics; DEAD-box RNA Helicases - metabolism; DNA helicase; Double-stranded RNA; dsRNA; Immune system; innate immunity; Insects; Interferon; Invertebrates; Life Sciences & Biomedicine - Other Topics; MicroRNAs; Molecular weight; Mutation; Phosphates; Protein Binding; Proteins; Ribonuclease III - chemistry; Ribonuclease III - genetics; Ribonuclease III - metabolism; RNA Helicases - chemistry; RNA Helicases - genetics; RNA Helicases - metabolism; RNA, Double-Stranded - metabolism; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; RNAi; Sedimentation & deposition; Structural Biology and Molecular Biophysics; translocation; Vertebrates; dsRNA; C. elegans; RNAi; translocation; chemical biology; innate immunity; antiviral; biochemistry; structural biology; autoinhibition; molecular biophysics
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.93979

Invertebrates use the endoribonuclease Dicer to cleave viral dsRNA during antiviral defense, while vertebrates use RIG-I-like Receptors (RLRs), which bind viral dsRNA to trigger an interferon response. While some invertebrate Dicers act alone during antiviral defense,
Dicer acts in a complex with a dsRNA binding protein called RDE-4, and an RLR ortholog called DRH-1. We used biochemical and structural techniques to provide mechanistic insight into how these proteins function together. We found RDE-4 is important for ATP-independent and ATP-dependent cleavage reactions, while helicase domains of both DCR-1 and DRH-1 contribute to ATP-dependent cleavage. DRH-1 plays the dominant role in ATP hydrolysis, and like mammalian RLRs, has an N-terminal domain that functions in autoinhibition. A cryo-EM structure indicates DRH-1 interacts with DCR-1's helicase domain, suggesting this interaction relieves autoinhibition. Our study unravels the mechanistic basis of the collaboration between two helicases from typically distinct innate immune defense pathways.