Two microbiome metabolites compete for tRNA modification to impact mammalian cell proliferation and translation quality control.

The microbiome affects eukaryotic host cells via many metabolites, including the well-studied queuine as substrate for host tRNA queuosine modification. The microbial metabolite pre-queuosine 1 (preQ) is produced in the bacterial tRNA queuosine biosynthesis pathway, with unknown effects on host cell biology. Here we show that preQ strongly represses cell proliferation in both human and mouse cells. Queuine reverses this effect by competing with preQ to modify the same tRNA. PreQ is detectable in the plasma and tissues of mice, and its injection suppresses tumour growth in a mouse cancer model. Mechanistically, preQ reduces cognate tRNA levels specifically, as well as codon-dependent translation of housekeeping genes. We identify the endoplasmic reticulum-localized inositol-requiring enzyme 1 (IRE1) ribonuclease as the enzyme responsible for the selective degradation of preQ-modified tRNAs on translating ribosomes. Our results identify two microbial metabolites competing for host tRNA modification, which elicits translation quality control and impacts cell proliferation.