Proposed RNA interference (RNAi) pathway of Haemonchus contortus. The genes predicted in H. contortus contain all of the previously identified core functional groups in nematode RNAi machinery , small RNA biosynthesis, double-stranded RNA (dsRNA) uptake and spreading, catalytic components, argonauts (AGO) of the RNA-induced silencing complex (RISC), RNAi inhibitors, and nuclear effectors. Genes present in H. contortus are represented by black codes, and those common to nematode RISC machinery are in gray. (A) Exogenous dsRNA and small interfering RNA (siRNA) enters cells via transporter SID-1. Internally produced secondary siRNA is spread to other cells via the transporter RSD-2. (B) Endogenous pre-microRNAs (pre-miRNAs) and siRNAs are produced in the nucleus, and exported to the cytosol via the nuclear export receptors XPO-1 and XPO-3. (C) Both the exogenous dsRNA and endogenous pre-miRNAs are cleaved by a dicer complex to produce siRNA and mature miRNA, respectively. (D) These RNAs are then bound to RISC, resulting in mRNA destruction or translational repression. (E) RNAi inhibitors can downregulate both siRNAs and miRNAs. (F) Secondary siRNAs produced by the catalytic components (MUT, SMF, and RRF) can contribute to downregulation of the target transcript. These siRNAs can also spread to other cells via (G) transporter RSD-2, and can be imported into the nucleus by (H) NRDE-3, in which they integrate to nuclear RISC to silence nascent RNA transcripts.