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PIWI pathway against viruses in insects

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Abstract Piwi‐interacting RNAs (piRNAs) are an animal‐specific class of small non‐coding RNAs that are generated via a biogenesis pathway distinct from small interfering RNAs (siRNAs) and microRNAs (miRNAs). There are variations in piRNA biogenesis that depend on several factors, such as the cell type (germline or soma), the organism, and the purpose for which they are being produced, such as transposon‐targeting, viral‐targeting, or gene‐derived piRNAs. Interestingly, the genes involved in the PIWI/piRNA pathway are more rapidly evolving compared with other RNA interference (RNAi) genes. In this review, the role of the piRNA pathway in the antiviral response is reviewed based on recent findings in insect models such as Drosophila, mosquitoes, midges and the silkworm, Bombyx mori. We extensively discuss the special features that characterize host‐virus piRNA responses with respect to the proteins and the genes involved, the viral piRNAs' sequence characteristics, the target strand orientation biases as well as the viral piRNA target hotspots across the viral genomes. This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > RNAi: Mechanisms of Action Regulatory RNAs/RNAi/Riboswitches > Biogenesis of Effector Small RNAs
Model of piRNA biogenesis in the fruitfly Drosophila melanogaster. In ovarian germline cells of Drosophila the piRNA pathway initiates from RNA polymerase II mediated transcription of piRNA clusters that produce the respective precursor piRNA (pre‐piRNA) transcripts in the nucleus. When driven to the cytoplasm where the primary piRNA biogenesis takes place, Vasa guides the pre‐piRNAs to Zuc endonuclease that is localized on the mitochondrial outer membrane, which cleaves them and produces the characteristic 1U signature at the 5′ end of the piRNA molecule. Indispensable for this step are also the mitochondria‐associated proteins Armi and Mino. The 1U‐piRNAs can then be guided to a Papi‐Piwi complex in the frame of the primary pathway to direct transcriptional/epigenetic silencing, or to Aub so that the Ping‐Pong amplification loop (secondary piRNA biogenesis) starts. In the nuage the 1U‐piRNAs are bound to Aub and then guide it to complementary transposon transcripts so that hybridization and slicing of them happens with the help of Zuc. The cleaved piRNA products with the characteristic Ping‐Pong signature of 10A are then bound to Ago3 which is stabilized by Papi and, similarly to Aub function, a search for complementary transposon transcripts is made so that hybridization and cleavage can occur. Krimper and Qin contribute to the correct Ping‐Pong cycle function in the nuage. Further processing of the mature piRNAs' 3′ ends can then be performed either by the 3′‐5′ exoribonuclease Nibbler and/or by methyltransferase HEN1. Following Zuc cleavage of the pre‐piRNA transposon transcript that is bound to Ago3, the 3′ end of the secondary piRNA and the 5′ end of the phased piRNA are created. Via an interaction between Piwi and Zuc on the mitochondrial surface, phased piRNAs can be then transported in complex with Piwi to other subcellular positions. An important step of the piRNA biogenesis is the methylation of PIWI proteins (Piwi, Ago3, Aub) by the methyltransferase dPMRT5 that is necessary for their modification to bear symmetrical dimethylarginine domains (sDMAs) so that they interact with the Tudor domains of other key piRNA pathway proteins and form functional complexes
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Model of piRNA biogenesis in the mosquito Aedes aegypti. Although the piRNA biogenesis mechanism has not yet been thoroughly studied in mosquitoes, it can be assumed that in somatic Aag2 cells derived from Ae. aegypti the piRNA pathway initiates from RNA polymerase II mediated transcription of piRNA clusters that produces the respective precursor piRNA (pre‐piRNA) transcripts in the nucleus. The piRNA pathway may also start upon an RNA viral infection, such that the single‐stranded viral RNA genome or the respective replication RNA intermediates may serve as alternative forms of precursor (v)piRNA transcripts. Alternatively, the viral RNA can be reversely transcribed and produce a viral DNA form that can then be integrated in the host genome and lead to the production of vDNA‐transcripts. In the cytoplasm where the primary piRNA biogenesis is assumed to take place, Piwi4 probably plays a key role by regulating the function of the core piRNA factors and the available RNA substrate levels, while it is also proposed to connect via an unknown mechanism the piRNA and siRNA pathways. Depending on the RNA substrate origin, the processing pathway to piRNAs varies. Data on gene‐derived and transposable element (TE)‐derived piRNAs so far show that they are mainly processed by Piwi5, Piwi6 and Ago3. With regard to the vpiRNA pathway, many similarities to the Ping‐Pong pathways of Drosophila and B. mori are observed. The whole Ping‐Pong procedure takes place in a perinuclear “nuage‐like” structure. Following the unknown primary biogenesis pathway, vpiRNAs bearing the characteristic 1U signature are bound to Piwi5 (or Piwi6) and the Ping‐Pong amplification loop (secondary piRNA biogenesis) starts. The 1U‐vpiRNAs/Piwi5 (Piwi6) complex scans for complementary transcripts to initiate hybridization and slicing. The cleaved piRNA products with the characteristic Ping‐Pong signature of 10A are then bound to Ago3 and, similarly to Piwi5 (or Piwi6) function, a search for complementary transcripts is carried out such that hybridization and cleavage can occur. Based on a SINV infection study, it has recently been shown that throughout the Ping‐Pong cycle, Yb protein is bound to Piwi5, while a Tudor‐domain protein named Veneno (Ven) interacts with Ago3 and forms a molecular scaffold with Yb and vasa to facilitate the production of the vpiRNAs
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Model of piRNA biogenesis in the silkworm Bombyx mori. In ovary‐derived BmN4 cells of B. mori, the piRNA pathway initiates from the RNA polymerase II mediated transcription of piRNA clusters that produces the respective precursor piRNA (pre‐piRNA) transcripts in the nucleus. When transported to the cytoplasm where the primary piRNA biogenesis takes place, the pre‐piRNAs are subjected to Zuc endonucleolytic cleavage on the mitochondrial outer membrane where the endonuclease is localized. Hsp90 then contributes to immature pre‐piRNA loading onto Siwi, which has previously been in complex with the heterodimer Spn‐E/Qin. Due to the intrinsic preference of Siwi's MID‐PIWI module for a uridine at the 5′ end of the piRNA molecule, the piRNAs bound to Siwi bear the characteristic 5’ U signature, and then the Ping‐Pong amplification loop (secondary piRNA biogenesis) starts. In the nuage the 1U‐piRNAs are bound to Siwi and then guided to complementary transposon transcripts so that hybridization and slicing of them happens with the help of Zuc. Guided also by Vasa, the cleaved piRNA products with the characteristic Ping‐Pong signature of 10A are then bound to Ago3 and, similarly to Siwi function, a search for complementary transposon transcripts is made so that hybridization and cleavage can occur. At this point Hsp90 helps to remove the Ago3 digestion byproducts. In the frame of the Ping‐Pong cycle, Siwi and Ago3 can form separately complexes with Papi and Zuc that are localized on the mitochondrial outer membrane, so that maturation of the piRNAs by other proteins, such as the 3′‐5′ exonuclease Trimmer or another unknown exonuclease, and the methyltransferase HEN1, can take place. According to a tertiary biogenesis pathway rarely observed in BmN4 cells, next to Zuc cleavage and Ago3 slicing of the Ago3‐bound pre‐piRNA transcript, an interaction between Siwi and Zuc may occur on mitochondria surface where phased piRNAs can be produced. An important step of the piRNA biogenesis is the methylation of PIWI proteins (Ago3, Siwi) by the methyltransferase dPMRT5 that is necessary for their symmetrical dimethylarginine (sDMA) modification so that they interact with the Tudor domains of other key piRNA pathway proteins. It remains to be further investigated if vpiRNAs are also generated/processed by the same mechanism as piRNAs from transposons, as described here. In that case, we speculate that the piRNA pathway might also start upon an RNA viral infection, so that the single‐stranded viral RNA genome or the respective replication RNA intermediates could serve as alternative forms of precursor vpiRNA transcripts
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Regulatory RNAs/RNAi/Riboswitches > Biogenesis of Effector Small RNAs
Regulatory RNAs/RNAi/Riboswitches > RNAi: Mechanisms of Action

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