Uptake of extracellular double-stranded RNA by SID-2.

Deborah L McEwan, Alexandra S Weisman, Craig P Hunter

Molecular cell 2012 Sep 14

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Ingested dsRNAs trigger RNA interference (RNAi) in many invertebrates, including the nematode Caenorhabditis elegans. Here we show that the C. elegans apical intestinal membrane protein SID-2 is required in C. elegans for the import of ingested dsRNA and that, when expressed in Drosophila S2 cells, SID-2 enables the uptake of dsRNAs. SID-2-dependent dsRNA transport requires an acidic extracellular environment and is selective for dsRNAs with at least 50 base pairs. Through structure-function analysis, we identify several SID-2 regions required for this activity, including three extracellular, positively charged histidines. Finally, we find that SID-2-dependent transport is inhibited by drugs that interfere with vesicle transport. Therefore, we propose that environmental dsRNAs are imported from the acidic intestinal lumen by SID-2 via endocytosis and are released from internalized vesicles in a secondary step mediated by the dsRNA channel SID-1. Similar multistep mechanisms may underlie the widespread observations of environmental RNAi. Copyright © 2012 Elsevier Inc. All rights reserved.

Citation

Deborah L McEwan, Alexandra S Weisman, Craig P Hunter. Uptake of extracellular double-stranded RNA by SID-2. Molecular cell. 2012 Sep 14;47(5):746-54