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.

OriginalsprogEngelsk
TidsskriftCell Metabolism
Vol/bind34
Udgave nummer12
Sider (fra-til)2036-2046.e8
Antal sider20
ISSN1550-4131
DOI
StatusUdgivet - 2022

Bibliografisk note

Funding Information:
Work in the Bekker-Jensen lab was supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement 863911 —PHYRIST). A.C.V., Z.G.-H., and C.C. received funding from the Novo Nordisk Foundation (grant numbers NNF20SA0064340 and NNF18CC0034900 ). D.G. received funding from the Swiss National Science Foundation (grant numbers 141735 and 179190 ).

Funding Information:
Work in the Bekker-Jensen lab was supported by the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement 863911—PHYRIST). A.C.V. Z.G.-H. and C.C. received funding from the Novo Nordisk Foundation (grant numbers NNF20SA0064340 and NNF18CC0034900). D.G. received funding from the Swiss National Science Foundation (grant numbers 141735 and 179190). S.B.-J. and C.C. conceived the study. G.S. A.V.G. A.C.V. L.R. M.S. S.C. R.D. C.N. F.S. M.B. A.R.L. S.H.B. K.L.A. and S.S.P. performed experiments and analyzed data. A.E.W. L.B.F. D.G. Z.G.-H. C.C. and S.B.-J. supervised experiments and analysis. S.B.-J. wrote the manuscript with input from D.G. The authors declare no competing interests.

Publisher Copyright:
© 2022 The Author(s)

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