Figure 4.

Proposed mechanisms of exogenous dsRNA cell-uptake, cell-to-cell and systemic movement in insects. Scavenger receptor-mediated clathrin-dependent endocytosis is the main pathway for cellular uptake of dsRNAs in midgut cells, although additional unknown factors may be involved in this process. The uptake is dependent on the dsRNA size, and nucleases in the digestive system may compromise the dsRNA stability. Unknown cellular factors mediate dsRNA egress from the late endosome; inefficient endosomal escape induces dsRNA degradation after endosome-lysosome fusion. In the cytoplasm, the dsRNAs mediate the silencing of endogenous host genes. dsRNAs, RNAi machinery and RNA intermediates can be transported to neighboring cells through cytoplasmic projections (TnTs) and possibly through tight junctions. Systemic movement to distant cells through hemolymph depends on exosomal encapsulation, and it has been proposed that it may also be mediated by dsRNA binding to apolipophorins. The interaction with these cellular components prevents their degradation by the hemolymph nucleases. Alterations in plasma membrane composition may be consequential in the uptake and distribution of the silencing signal. Chup-1/Tag-130, cholesterol uptake protein 1; HF?, unknown host factor; RISC, RNA-induced silencing complex; siRNA, small interfering RNA; TnTs, tunneling nanotubes; and vATPase, Vacuolar-type ATPase.