Cell Metab.: co-auth.: group Gatfield

Cell Metab. 2022 Nov 8;S1550-4131(22)00489-2. doi: 10.1016/j.cmet.2022.10.011. Online ahead of print.

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

Goda Snieckute 1Aitana Victoria Genzor 1Anna Constance Vind 1Laura Ryder 1Mark Stoneley 2Sébastien Chamois 3René Dreos 3Cathrine Nordgaard 1Frederike Sass 4Melanie Blasius 1Aida Rodríguez López 5Sólveig Hlín Brynjólfsdóttir 5Kasper Langebjerg Andersen 6Anne E Willis 2Lisa B Frankel 7Steen Seier Poulsen 8David Gatfield 3Zachary Gerhart-Hines 4Christoffer Clemmensen 4Simon Bekker-Jensen 9


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.

Keywords: AMPK; FGF21; ZAK-alpha; amino acid starvation; mTOR; metabolic regulation; mouse models; ribosome collision; ribotoxic stress response.