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Contributed by Dieter Söll, May 23, 2018 (sent for review February 21, 2018; reviewed by Michael Ibba and Xiang-Lei Yang)
Significance
Microsporidia are poorly treatable eukaryotic pathogens that threaten human health and industrially valuable insects and fish, yet we are only beginning to understand the complex biology of these emerging pathogens. Here we combine bioinformatics, biochemistry, and mass spectrometry analyses to show that Microsporidia carry an error-prone machinery of protein synthesis, and that their protein synthesis is accompanied by a remarkable number of translation errors. This finding reveals a previously unknown aspect of protein synthesis in these emerging parasites and creates a potential opportunity to use the defective protein synthesis machinery as a therapeutic target to treat microsporidia infections.
Abstract
Microsporidia are parasitic fungi-like organisms that invade the interior of living cells and cause chronic disorders in a broad range of animals, including humans. These pathogens have the tiniest known genomes among eukaryotic species, for which they serve as a model for exploring the phenomenon of genome reduction in obligate intracellular parasites. Here we report a case study to show an apparent effect of overall genome reduction on the primary structure and activity of aminoacyl-tRNA synthetases, indispensable cellular proteins required for protein synthesis. We find that most microsporidian synthetases lack regulatory and eukaryote-specific appended domains and have a high degree of sequence variability in tRNA-binding and catalytic domains. In one synthetase, LeuRS, an apparent sequence degeneration annihilates the editing domain, a catalytic center responsible for the accurate selection of leucine for protein synthesis. Unlike accurate LeuRS synthetases from other eukaryotic species, microsporidian LeuRS is error-prone: apart from leucine, it occasionally uses its near-cognate substrates, such as norvaline, isoleucine, valine, and methionine. Mass spectrometry analysis of the microsporidium Vavraia culicis proteome reveals that nearly 6% of leucine residues are erroneously replaced by other amino acids. This remarkably high frequency of mistranslation is not limited to leucine codons and appears to be a general property of protein synthesis in microsporidian parasites. Taken together, our findings reveal that the microsporidian protein synthesis machinery is editing-deficient, and that the proteome of microsporidian parasites is more diverse than would be anticipated based on their genome sequences.
Footnotes
- ↵1To whom correspondence should be addressed. Email: dieter.soll{at}yale.edu.
Author contributions: S.V.M., M.J.S., D.J.P., and D.S. designed research; S.V.M., K.D.R., D.O., A.M., and C.T. performed research; N.D.S., J.J.B., and C.T. contributed new reagents/analytic tools; S.V.M., K.D.R., and D.S. analyzed data; and S.V.M. and D.S. wrote the paper.
Reviewers: M.I., The Ohio State University; and X.-L.Y., The Scripps Research Institute.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1803208115/-/DCSupplemental.
Published under the PNAS license.
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Error-prone protein synthesis in parasites with the smallest eukaryotic genome
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