Zhang Wen, Lahry Kuldeep, Cipurko Denis, Huang Sihao, Zbihley Olivia, Sevilleja Amanda M, Rudzka Dominika, Frietze Luke R, Assari Mahdi, Katanski Christopher D, Singh Marisha, Attina Aurore, Guillorit Hélène, Watkins Christopher P, Gourlain Delphine, Varlet Didier, Falconi Jennifer, Djiane Alexandre, Hirtz Christophe, Chen Hankui, Macari Françoise, Johnson Katherine, Chevrier Nicolas, David Alexandre, Pan Tao
Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA.
IRCM, University of Montpellier, Montpellier, France.
Nat Cell Biol. 2025 Sep 16. doi: 10.1038/s41556-025-01750-6.
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.
微生物组通过许多代谢产物影响真核宿主细胞，包括研究充分的 queuine，它作为宿主 tRNA 反密码子摆动核苷修饰的底物。微生物代谢产物前 queuosine 1（preQ）在细菌 tRNA 反密码子摆动核苷生物合成途径中产生，对宿主细胞生物学的影响尚不清楚。在这里，我们表明 preQ 强烈抑制人和小鼠细胞的增殖。Queuine 通过与 preQ 竞争修饰相同的 tRNA 来逆转这种作用。在小鼠的血浆和组织中可检测到 preQ，并且其注射可抑制小鼠癌症模型中的肿瘤生长。从机制上讲，preQ 特异性地降低同源 tRNA 水平以及管家基因的密码子依赖性翻译。我们确定内质网定位的肌醇需求酶 1（IRE1）核糖核酸酶是负责在翻译核糖体上选择性降解 preQ 修饰的 tRNA 的酶。我们的结果确定了两种竞争宿主 tRNA 修饰的微生物代谢产物，它们引发翻译质量控制并影响细胞增殖。
