APA
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Karampelias, C., Watt, K., Mattsson, C. L., Ruiz, A., Rezanejad, H., Mi, J., … Andersson, O. (2022). MNK2 deficiency potentiates β-cell regeneration via translational regulation. Nature Chemical Biology.
Chicago/Turabian
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Karampelias, Christos, Kathleen Watt, Charlotte L. Mattsson, Angel Ruiz, Habib Rezanejad, J. Mi, Xiaojing Liu, et al. “MNK2 Deficiency Potentiates β-Cell Regeneration via Translational Regulation.” Nature Chemical Biology (2022).
MLA
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Karampelias, Christos, et al. “MNK2 Deficiency Potentiates β-Cell Regeneration via Translational Regulation.” Nature Chemical Biology, 2022.
BibTeX Click to copy
@article{christos2022a,
title = {MNK2 deficiency potentiates β-cell regeneration via translational regulation},
year = {2022},
journal = {Nature Chemical Biology},
author = {Karampelias, Christos and Watt, Kathleen and Mattsson, Charlotte L. and Ruiz, Angel and Rezanejad, Habib and Mi, J. and Liu, Xiaojing and Chu, Lianhe and Locasale, J. and Korbutt, G. and Rovira, M. and Larsson, O. and Andersson, Olov}
}
Regenerating pancreatic β-cells is a potential curative approach for diabetes. We previously identified the small molecule CID661578 as a potent inducer of β-cell regeneration, but its target and mechanism of action have remained unknown. We now screened 257 million yeast clones and determined that CID661578 targets MAP kinase-interacting serine/threonine kinase 2 (MNK2), an interaction we genetically validated in vivo. CID661578 increased β-cell neogenesis from ductal cells in zebrafish, neonatal pig islet aggregates and human pancreatic ductal organoids. Mechanistically, we found that CID661578 boosts protein synthesis and regeneration by blocking MNK2 from binding eIF4G in the translation initiation complex at the mRNA cap. Unexpectedly, this blocking activity augmented eIF4E phosphorylation depending on MNK1 and bolstered the interaction between eIF4E and eIF4G, which is necessary for both hypertranslation and β-cell regeneration. Taken together, our findings demonstrate a targetable role of MNK2-controlled translation in β-cell regeneration, a role that warrants further investigation in diabetes. MNK2 was identified as the target of a small molecule named CID661578 that can stimulate pancreatic β-cell generation in zebrafish, pig and human organoids. CID661578 prevents MNK2 from binding to eIF4G in the translation initiation complex.