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  1. Evaluation Summary:

    In this important paper, Chen and colleagues identify a species of fungus, Ophiocordyceps sp. BRM1, that is able to grow on Aglaia sp. plants despite their production of rocaglate inhibitors of the eIF4A translation initiation factor. Through a series of solid experiments, the authors identify an amino acid substitution encoded in the fungal eIF4A gene that preserves eIF4A activity in the presence of these compounds. The authors conclude the substitution evolved to bypass this defense mechanism, similar to the way in which the plant itself bypasses it. The work will be of interest to fungal biologists and colleagues studying plant-microbe interactions.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

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  2. Reviewer #1 (Public Review):

    The work suggests an evolutionary "arms race" between Ophiocordyceps BRM1 and Aglaia and that acquisition of eIF4A-H153G was a key step permitting the fungus to colonize the plant during its life cycle. Functional experiments are convincing in terms of differential sensitivity of translation to repression by rocaglates when H153G (or equivalent) is introduced to various eIF4A isoforms from multiple species in cell-free reporter systems and in engineered fungal strains. Although BRM1 could not be genetically engineered, the authors introduced H153G or wild-type eIF4A into related C. orbiculare species and found the substitution reversed translational repression phenotypes of rocaglates. H153G also permitted growth on rocaglate-treated cucumber leaves in contrast to wild-type. Overall the work demonstrates a specific AA substitution analogous to change in the Aglaia plant itself that may permit Ophiocordyceps BRM1 to grow on the plant, bypassing a key defense mechanism. The H153 polymorphism in Ophiocordyceps BRM1 suggests growth of Aglaia species is an obligate part of the fungus' life cycle, and that it evolved to fill this niche in a way that no other described species has done. However, since the organism is also known to parasitize ant species, it is not entirely clear from the data presented that growth on Aglaia is an obligate step. Regardless, the report is highly suggestive of a specific AA substitution having evolved in a fugal species to bypass a specific plant defense strategy.

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  3. Reviewer #2 (Public Review):

    This manuscript from Chen, Kumakura et al. continues their pursuit of the molecular understanding of RocA as a translation inhibitor. In particular, this body of work expands on how RocA fits into the "bigger picture" of biology as Chen, Kumakura et al. define how a fungus (Ophiocordyceps) that infects the plant (Agalia) that naturally produces RocA. There are several new conclusions provided by the authors that are strongly supported by the data. The de novo construction of Ophiocordyceps sp. BRM1 was essential for finding the Phe163Gly substitution (human position) that elicits Ophiocordyceps resistance to RocA. This conclusion was supported by strong biochemical data (RNA-binding affinity with RocA and ATP analogs) with recombinant protein and in vivo translation data via ribosome profiling. The authors turned to a more genetically attractable fungus (C. orbiculare) and used CRISPR-Cas9 mediated gene editing to make a His153Gly substitution (human position), which aligns with the Phe163Gly substitution in Ophiocordyceps, to demonstrate RocA sensitivity was depending on this single substitution. The discussion is thoughtful and ties in with their previous work with eIF4A1 and DDX3. In general, the manuscript is strong and well-written and would be interesting to a wide audience (those in translational control, ecology of plants-fungus relationships).

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