Fig. 2

Immune-related signalling pathways in mosquitos. In the Toll pathway, the pathogen first binds to PPRs, which triggers the proteolytic cleavage of the cytokine Späetzle and then activates the Toll receptor to which it binds. Subsequent triggering of signals via the adaptor proteins MyD88, Tube, and Pelle leads to the phosphorylation and degradation of the Cactus protein, an inhibitor of Rel1. Finally, the degradation of the Cactus protein translocates Rel1 to the nucleus and activates the Toll pathway to regulate gene transcription. In the IMD pathway, pathogens bind to PGRP-LC and PGRP-LE ligands and trigger signalling by various cysteoaspartases and kinases. One branch triggers the JNK signalling pathway, while the other triggers signals via IMD, FADD, and Dredd, which mediate phosphorylation, as well as the cleavage of Rel2. Caspar proteins act as negative regulators of the IMD pathway. Subsequent translocation of Rel2 to the nucleus activates the IMD pathway to regulate gene transcription. The JAK-STAT pathway is triggered by the binding of Unpaired (Upd) to the receptor protein Dome, which activates the receptor-associated Hop Janus kinase. Activated Hop kinases phosphorylate each other and subsequently recruit phosphorylated STAT transcription factors and form dimers. Phosphorylated STAT dimers are translocated to the nucleus to activate JAK-STAT-regulated transcription. RNAi pathways include the siRNA pathway, miRNA pathway, and piRNA pathway. In the siRNA pathway, exogenous dsRNA is recognised by the RNA-binding structural domain of Dicer2 and is sheared into small dsRNA of 21–28 nt. The Ago2 protein leads to the silencing of complementary transcripts in the cell by degrading or inhibiting the translation of sRNAs by binding to them, and R2D2 is involved in the delivery of the siRNA guide strand from Dicer2 to Ago2. In the miRNA pathway, pri-miRNAs are produced in the nucleus using the genome and processed by Drosha and Pasha proteins to be converted into pre-miRNAs. Pre-miRNA is translocated to the cytoplasm via export protein 5, where it is further processed by the Dicer1 and Loqs complexes to form miRNA-miRNA duplexes, followed by the formation of guide RNAs via Ago1 and Ago2, leading to degradation of the target mRNAs and transcriptional repression through the RISC complexes (composed of Ago2 or Ago1, VIG, TSN, Rp, C3PO, and other unknown proteins). In the piRNA pathway, after viRNA enters the host cell, it binds to unknown PIWI proteins (PIWI 1–7) and directly enters the ping-pong cycle to bind to the complementary antisense RNA of Piwi5 for shearing and methylation. The antisense RNA is then released to bind to an unknown PIWI protein. The processed positive-sense RNA then binds to Ago3 to form a long-stranded antisense piRNA precursor, and the antisense piRNA precursor is sheared and methylated to form an antisense piRNA release, which binds to Piwi5 to start another round of the ping-pong cycle. The other viRNA undergoes reverse transcription and replication and then enters the host cell nucleus to integrate into the genome, where it is subsequently transcribed and translocated into the cytoplasm to enter the ping-pong cycle