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

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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.

Original languageEnglish
JournalCell Metabolism
Volume34
Issue number12
Pages (from-to)2036-2046.e8
Number of pages20
ISSN1550-4131
DOIs
Publication statusPublished - 2022

Bibliographical note

Publisher Copyright:
© 2022 The Author(s)

    Research areas

  • amino acid starvation, AMPK, FGF21, metabolic regulation, mouse models, mTOR, ribosome collision, ribotoxic stress response, ZAK-alpha

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