Protection against microbial infection in eukaryotes is provided by diverse cellular and molecular mechanisms. Here, we present a comparative view of the antiviral activity of virus-derived small interfering RNAs in fungi, plants, invertebrates and mammals, detailing the mechanisms for their production, amplification and activity. We also highlight the recent discovery of viral PIWI-interacting RNAs in animals and a new role for mobile host and pathogen small RNAs in plant defence against eukaryotic pathogens. In turn, viruses that infect plants, insects and mammals, as well as eukaryotic pathogens of plants, have evolved specific virulence proteins that suppress RNA interference (RNAi). Together, these advances suggest that an antimicrobial function of the RNAi pathway is conserved across eukaryotic kingdoms.
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The authors acknowledge research support by grants from the US National Institute of Allergy and Infectious Diseases and National Institute of General Medical Sciences, the US Department of Agriculture and the Agricultural Experimental Station of the University of California, Riverside (to S.-W.D.), the Fujian Agriculture and Forestry University (to Z.G.) and the National Natural Science Foundation of China (to Y.L.). Because of space limitations, the authors have often cited reviews rather than primary research papers. They apologize to those investigators whose original papers have not been cited.
S.-W.D and Y.L. declare competing interests. They are named on one patent application, which is pending, regarding the use of small interfering RNAs as a new mechanism of mammalian antiviral immunity.
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- Small interfering RNAs
(siRNAs). Short double-stranded RNAs of 20–23 nucleotides in length with 2-nucleotide 3′ overhangs that have 5′-monophosphate and 3′-hydroxyl termini and are cleaved from long perfectly complementary double-stranded RNA precursors by Dicer. The guide strand of siRNA in the RNA-induced silencing complex directs RNA interference in a sequence-specific manner.
(miRNAs). Small (~21–23 nucleotides in length), single-stranded RNA molecules that have 5′-monophosphate and 3′-hydroxyl termini, are cleaved from long hairpin RNA precursors by Dicer, and specifically inhibit gene expression in the RNA-induced silencing complex in a sequence-specific manner.
- PIWI-interacting RNAs
(piRNAs). Single-stranded RNAs of 23–33 nucleotides in length that have 5′-monophosphate and 3′-hydroxyl termini and are produced from single-stranded RNA precursors in a Dicer-independent manner. They are found in animals and not in plants, possibly because plant genomes do not encode any Argonaute (AGO) protein of the PIWI subfamily that is necessary for piRNA biogenesis. piRNAs guide specific cleavages of target RNAs by PIWI proteins.
- Argonaute protein
(AGO protein). A member of a family of proteins that associate with small interfering RNAs, microRNAs or PIWI-interacting RNAs to mediate RNA interference. AGO proteins contain an amino-terminal PAZ domain and a central domain that bind the 3′ end and 5′ phosphate of the guide strand small RNA, respectively, as well as a carboxy-terminal PIWI domain that has structural similarity to RNase H. A subset of AGO proteins have endonuclease activity, whereas most mammalian AGO subfamily members only silence translation.
- RNA interference
(RNAi). A process of RNA sequence homology-dependent gene silencing guided by small silencing RNAs such as small interfering RNAs, microRNAs or PIWI-interacting RNAs bound to an Argonaute (AGO) protein-containing multicomponent ribonucleoprotein complex.
- RNA-induced silencing complex
(RISC). A multicomponent ribonucleoprotein complex, comprising the guide strand of microRNAs or small interfering RNAs, Argonaute (AGO) proteins and cofactors, that silences the expression of proteins from target mRNAs by either RNA cleavage or RNA decay and/or translational repression depending on the complementarity of mRNA sequences to the packaged small RNAs.
- IMD signalling
One of two innate immune nuclear factor-κB signalling pathways in Drosophila melanogaster. The IMD pathway responds to DAP-type peptidoglycan from Gram-negative, and some Gram-positive, bacteria. This leads to the rapid and robust production of antimicrobial peptides.
- MIKCC-type MADS box proteins
A group of transcription factors that contain the MADS box, which is involved in DNA binding and dimerization with other MADS box proteins, and three additional conserved domains — the intervening domain, the keratin domain and the carboxy-terminal domain.
A subclass of transposons that amplify themselves in a genome through a process that involves the reverse transcription of RNA to DNA by a reverse transcriptase that is encoded by a retrotransposon.
Also known as ‘jumping genes’ and ‘selfish DNA’; DNA sequences that encode transposases, the enzymes that are required to excise the transposon from its original chromosomal location and to integrate it in a different position within the genome. The ends of transposons consist of DNA repeats that function as recognition sites for the transposase itself.
Cells found within the haemolymph of an insect that are equivalent to the blood cells in vertebrates. Different types of haemocyte are plasmatocytes, crystal cells and lamellocytes. These cells have important roles in immunity through the secretion of cytokines and the phagocytic clearance of invaders.
- RNA slicing
The specific endonucleolytic cleavage of mRNA molecules that contain a sequence complementary to the guide strand small RNA (small interfering RNA, microRNA or PIWI-interacting RNA) in the RNA-induced silencing complex by the PIWI domain of a subset of Argonaute (AGO) proteins. The cleavage occurs in the middle of the region that is base paired with the guide strand.
- Protein kinase R
One of the cytosolic sensors of viral and artificial double-stranded RNA in mammals, which, upon activation, can phosphorylate the eukaryotic translation initiation factor eIF2α, leading to global translation shutdown and apoptosis.
- Ping-pong amplification
A model proposed for the biogenesis of animal primary and secondary PIWI-interacting RNAs.
- Oomycete pathogens
A distinct phylogenetic lineage of filamentous fungus-like eukaryotic microorganisms, which include important plant pathogens such as those that cause devastating diseases of potato plants.
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Guo, Z., Li, Y. & Ding, SW. Small RNA-based antimicrobial immunity. Nat Rev Immunol 19, 31–44 (2019). https://doi.org/10.1038/s41577-018-0071-x
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