Uptake of extracellular double-stranded RNA by SID-2

Mol Cell. 2012 Sep 14;47(5):746-54. doi: 10.1016/j.molcel.2012.07.014. Epub 2012 Aug 16.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Caenorhabditis elegans / cytology
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans Proteins / antagonists & inhibitors
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Cells, Cultured
  • Drosophila / cytology
  • Drosophila / metabolism
  • Endocytosis
  • Histidine / metabolism
  • Hydrogen-Ion Concentration
  • Macrolides / pharmacology
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • RNA, Double-Stranded / chemical synthesis
  • RNA, Double-Stranded / chemistry
  • RNA, Double-Stranded / metabolism*
  • Structure-Activity Relationship
  • Thiazolidines / pharmacology


  • Bridged Bicyclo Compounds, Heterocyclic
  • Caenorhabditis elegans Proteins
  • Macrolides
  • Membrane Proteins
  • RNA, Double-Stranded
  • SID-2 protein, C elegans
  • Thiazolidines
  • Histidine
  • bafilomycin A1
  • latrunculin A