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  1. eLife assessment

    This is an important study that resolves a controversy about a proposed molecular linkage between the fields of mechanobiology and RNA signaling. While prior research had claimed that a specific mechanosensitive ion channel in the gut responds to a specific fecal RNA, this study provides compelling evidence that the mechanosensitive ion channel does not respond to the RNA.

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  2. Reviewer #1 (Public Review):

    In 2020, Sugisawa et al. reported that Piezo1ion channels can be activated by ssRNAs, both synthetic and derived from fecal matter, suggesting that these may be the first identified natural ligands to agonize Piezo channels. Nickolls et al., provide a careful and rigorous investigation of the effect of ssRNAs and fecal extracts on Piezo channel activity in three cell lines, using both calcium imaging and electrophysiology. They find that Piezo1 is not responsive to ssRNAs nor responsible for calcium flux in response to fecal extracts in HEK293 and RIN14b cells. Overall, this study addresses the question of ssRNAs as a Piezo ligand clearly and thoroughly, with rigorous, well-controlled experiments. Overall, I am excited about this study as a necessary clarification for the field of Piezo mechanosensation.

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  3. Reviewer #2 (Public Review):

    In the present study, the authors have combined calcium imaging and electrophysiology to systematically replicate the previously reported finding that the mechanical activation ion channel Piezo1 might also serve as a gut RNA sensor. The authors have employed multiple cell lines, knockout of endogenous Piezo1, and heterologous overexpression of Piezo1, Yoda1 as a positive control for chemical activation of Piezo1, and similar dosage of ssRNA used in the previous study, but clearly did not replicate the finding that ssRNA can specifically activate Piezo1. The experiments have been well designed and data quality is high. The data support the conclusion that Piezo1 is not a receptor for ssRNA in the gut.

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  4. Reviewer #3 (Public Review):

    This study investigates the recently published findings by Sugisawa et al that microbial ssRNA40, a known agonist for the immune surveillance system activates the mechanically gated ion channel Piezo1. In addition to providing mechanistic insights into the study, this finding also had much broader implications as it suggested a novel role for the channel as a physiological receptor for ssRNA. Although there is nothing that prevents Piezo1 from carrying out such a role in principle, the finding caused a great deal of interest and professional skepticism among Piezo researchers and, more broadly, in the field of mechanobiology. This manuscript set out to reproduce the main findings of Sugisawa et al using the same approaches, and in addition utilized other techniques to address potential differences in experimental conditions. In summary, the authors failed to reproduce the major Piezo1-related findings reported by Sugisawa et al, while all the new experiments pointed to the absence of a functional interaction between ssRNA40 and Piezo1. The study is well-designed, with appropriate controls and statistical analyses.

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