丹麦哥本哈根大学Simon Bekker-Jensen团队近期取得重要工作进展，他们研究发现核糖体停滞是核糖毒性应激反应代谢调节的信号。相关论文2022年11月15日在线发表于《细胞—代谢》杂志上。

研究人员发现，核糖体的停滞足以激活ZAKα。在氨基酸剥夺和营养饥饿的反应中，RSR影响细胞、线虫和小鼠的代谢反应。这些模型系统中，RSR调节的反应包括AMPK和mTOR信号的调节、饥饿条件下的生存、应激激素的产生和血糖控制的调节。此外，ZAK^−/− 雄性小鼠呈现瘦弱的表型。这一研究工作强调受损的核糖体作为代谢信号，并证明RSR信号在代谢调节中的作用。

据介绍，翻译的损伤可导致核糖体的碰撞，促进多个核糖体应力监测通路的激活，其中包括核糖毒性应激反应（RSR）， MAP3K-ZAKα的核糖体感应导致p38和JNK激酶的激活。目前，关于核糖体损伤和下游RSR信号通路的生理影响仍然还不清楚。

附：英文原文

Title: Ribosome stalling is a signal for metabolic regulation by the ribotoxic stress response

Author: Goda Snieckute, Aitana Victoria Genzor, Anna Constance Vind, Laura Ryder, Mark Stoneley, Sébastien Chamois, René Dreos, Cathrine Nordgaard, Frederike Sass, Melanie Blasius, Aida Rodríguez López, Sólveig Hlín Brynjólfsdóttir, Kasper Langebjerg Andersen, Anne E. Willis, Lisa B. Frankel, Steen Seier Poulsen, David Gatfield, Zachary Gerhart-Hines, Christoffer Clemmensen, Simon Bekker-Jensen

Issue&Volume: 2022-11-15

Abstract: Impairment of translation can lead to collisions of ribosomes, which constitute an activation platform for several ribosomal stress-surveillance pathways. Among these is the ribotoxic stress response (RSR), where ribosomal sensing by the MAP3K ZAKα leads to activation of p38 and JNK kinases. Despite these insights, the physiological ramifications of ribosomal impairment and downstream RSR signaling remain elusive. Here, we show that stalling of ribosomes is sufficient to activate ZAKα. In response to amino acid deprivation and full nutrient starvation, RSR impacts on the ensuing metabolic responses in cells, nematodes, and mice. The RSR-regulated responses in these model systems include regulation of AMPK and mTOR signaling, survival under starvation conditions, stress hormone production, and regulation of blood sugar control. In addition, ZAK/ male mice present a lean phenotype. Our work highlights impaired ribosomes as metabolic signals and demonstrates a role for RSR signaling in metabolic regulation.

DOI: 10.1016/j.cmet.2022.10.011

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(22)00489-2