RNA Sensing by Gut Piezo1 Is Essential for Systemic Serotonin Synthesis

Abstract

Highlights d Intestinal epithelium-specific Piezo1 deletion disturbs gut and bone homeostasis d Fecal ssRNA is a natural ligand of Piezo1 d Colonic infusion of RNase A suppresses gut motility and increases bone mass d Intestinal ssRNA-Piezo1 axis is a critical factor in systemic 5-HT synthesis

RNA and the PIEZO force sensor

“…It led the authors to speculate about non-mechanical activators of PIEZO1 and for this they turned to the microbiome, encouraged by finding that antibiotics also reduced 5-HT and gut motility. 1 Filtered fecal solution acutely evoked intracellular Ca 2+ elevations in cultured epithelial cells, as expected if a PIEZO1 activator was present. The amplitude of the response was smaller than that of Yoda1, but clearly PIEZO1 dependent.…”

“…A striking feature of this new paper 1 is the authors’ observation that Tph1 expression was induced by cyclical stretch via a mechanism that was PIEZO1 independent but PIEZO2 dependent, suggesting PIEZO2 (see also 6 ) and not PIEZO1 as the force sensor in this situation. This was despite the fact that Yoda1, a synthetic chemical agonist of PIEZO1 but not PIEZO2, 7 mimicked the effect of stretch on Tph1 expression.…”

“…After finding evidence of PIEZO1 expression in intestinal epithelium, Sugisawa et al generated mice in which PIEZO1 was disrupted in epithelial chemosensory cells. 1 In these mice they found slower gut transit times and protection against features of colitis in a model of this disease. 5-HT (serotonin) was considered as a potential intermediate.…”

“…Sugisawa et al’s extensive work on mice and cultured cells has led them to proposals that could profoundly change thinking about intestinal biology and how RNA is sensed. 1 At the heart of their work is a protein called PIEZO1, which first came to prominence a decade ago as one of two unusual membrane proteins (PIEZO1 and PIEZO2). These proteins separately form large Ca 2+ -permeable non-selective cation channels with remarkable abilities to sense and respond to mechanical forces such as membrane stretch 2 – 5 (Fig.…”

“… 3 , 5 Even with Yoda1 it is thought that it acts by enhancing the effect of endogenous force already exerted on the channel, rather than as a stand-alone agonist. 7 Sugisawa et al’s work 1 pressures us to reflect on this force-centered view of PIEZO.…”