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RNA toxins: mediators of stress adaptation and pathogen defense

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Abstract RNA toxins are a group of enzymes primarily synthesized by bacteria, fungi, and plants that either cleave or depurinate RNA molecules. These proteins may be divided according to their RNA substrates: ribotoxins are nucleases that cleave ribosomal RNA (rRNA), ribosome inactivating proteins are glycosidases that remove a base from rRNA, messenger RNA (mRNA) interferases are nucleases that cleave mRNAs, and anticodon nucleases cleave transfer RNAs (tRNAs). These modifications to the RNAs may substantially alter gene expression and translation rates. Given that some of these enzymes cause cell death, it has been suggested that they function mainly in defense, either to kill competing cells or to elicit suicide and thereby limit pathogen spread from infected cells. Although good correlations have been drawn between their enzymatic functions and toxicity, recent work has shown that some RNA toxins cause apoptosis in the absence of damage to RNA and that defense against pathogens can be achieved without host cell death. Moreover, a decrease in cellular translation rate, insufficient to cause cell death, allows some organisms to adapt to stress and environmental change. Although ascribing effects observed in vitro to the roles of these toxins in nature has been challenging, recent results have expanded our understanding of their modes of action, and emphasized the importance of these toxins in development, adaptation to stress and defense against pathogens. WIREs RNA 2011 2 890–903 DOI: 10.1002/wrna.99 This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications RNA Turnover and Surveillance > Regulation of RNA Stability

Effect of (+)‐strand viral RNA depurination. (a) Ribosome stalling. Depurination (red star) of viral positive‐strand (+) genomic RNA (blue solid line) causes the host ribosome (yellow spheres) to stall at the abasic nucleotide and inhibits the synthesis of viral regulatory and structural proteins. (b) Polymerase stalling. Depurination of positive‐strand (+) genomic RNA causes the RNA polymerase to stall at the abasic nucleotide, preventing the production of full‐length negative‐strand (−) RNA required as template for the synthesis of positive‐strand (+) progeny RNA. (c) Coat protein binding. Depurination of positive‐strand (+) RNA reduces the affinity of viral coat protein (purple circles) for viral RNA and inhibits the encapsidation of this RNA into virus particles.

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Schematic diagram outlining entry and processing of colicin E5, colicin D, and zymocin. (a) The N‐terminal domain (NTD) of both colicin E5 and colicin D allow entrance through the cell wall via the BtuB and FepA surface receptors, respectively. Colicin D is proposed to be cleaved by the inner membrane peptidase LepB as it crosses the periplasmic space and enters the cytosol, yielding D‐CRD. It is not clear how or if colicin E5 undergoes cleavage. Once in the cytosol, E5‐CRD and D‐CRD cleave specific tRNA species leading to cell cycle arrest and cell death. (b) Zymocin (heterotrimer), uses its α and β subunits to interact with chitin domains on the cell surface and facilitate entry through the plasma membrane into the cytosol via the H+ pump encoded by the PMA1/KTI10 gene. Once in the cytosol, the γ subunit cleaves specific tRNA species leading to cell cycle arrest and cell death in susceptible cells.

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Regulation of the mRNA interferase MazF‐mx and transcription activator MrpC during Myxococcus xanthus development. (a) During vegetative growth, dimers of the MazF‐mx toxin (red circles) are bound by MrpC (blue triangles), which functions as the antitoxin. Remaining MrpC is negatively regulated through phosphorylation by a protein kinase cascade that prevents its ability to activate transcription from the MazF‐mx and MrpC promoters. (b) Upon introduction of stress, the developmental program is activated and the kinase cascade is turned off. MrpC undergoes proteolytic processing to MrpC2, which cannot be phosphorylated. MazF‐mx and MrpC promoters are upregulated and the toxin accumulates but is maintained by the antitoxin. (c) Before sporulation is induced, the majority of the population undergoes autolysis through activation of mRNA interferases, which cleave free and translating mRNAs (yellow spheres indicate ribosomes). MrpC and MrpC2 are proposed to be degraded by a cellular protease, releasing MazF‐mx to cleave target mRNAs at specific sequences.

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RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
RNA Turnover and Surveillance > Regulation of RNA Stability

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