MNK2 deficiency potentiates β-cell regeneration via translational regulation

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...

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Autores principales: Karampelias, Christos, Watt, Kathleen, Mattsson, Charlotte L., Ruiz, Ángel Fernández, Rezanejad, Habib, Mi, Jiarui, Liu, Xiaojing, Chu, Lianhe, Locasale, Jason W., Korbutt, Gregory S., Rovira, Meritxell, Larsson, Ola, Andersson, Olov
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group US 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7613404/
https://www.ncbi.nlm.nih.gov/pubmed/35697798
http://dx.doi.org/10.1038/s41589-022-01047-x
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author Karampelias, Christos
Watt, Kathleen
Mattsson, Charlotte L.
Ruiz, Ángel Fernández
Rezanejad, Habib
Mi, Jiarui
Liu, Xiaojing
Chu, Lianhe
Locasale, Jason W.
Korbutt, Gregory S.
Rovira, Meritxell
Larsson, Ola
Andersson, Olov
author_facet Karampelias, Christos
Watt, Kathleen
Mattsson, Charlotte L.
Ruiz, Ángel Fernández
Rezanejad, Habib
Mi, Jiarui
Liu, Xiaojing
Chu, Lianhe
Locasale, Jason W.
Korbutt, Gregory S.
Rovira, Meritxell
Larsson, Ola
Andersson, Olov
author_sort Karampelias, Christos
collection PubMed
description 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. [Image: see text]
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spelling pubmed-76134042022-08-24 MNK2 deficiency potentiates β-cell regeneration via translational regulation Karampelias, Christos Watt, Kathleen Mattsson, Charlotte L. Ruiz, Ángel Fernández Rezanejad, Habib Mi, Jiarui Liu, Xiaojing Chu, Lianhe Locasale, Jason W. Korbutt, Gregory S. Rovira, Meritxell Larsson, Ola Andersson, Olov Nat Chem Biol Article 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. [Image: see text] Nature Publishing Group US 2022-06-13 2022 /pmc/articles/PMC7613404/ /pubmed/35697798 http://dx.doi.org/10.1038/s41589-022-01047-x Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Karampelias, Christos
Watt, Kathleen
Mattsson, Charlotte L.
Ruiz, Ángel Fernández
Rezanejad, Habib
Mi, Jiarui
Liu, Xiaojing
Chu, Lianhe
Locasale, Jason W.
Korbutt, Gregory S.
Rovira, Meritxell
Larsson, Ola
Andersson, Olov
MNK2 deficiency potentiates β-cell regeneration via translational regulation
title MNK2 deficiency potentiates β-cell regeneration via translational regulation
title_full MNK2 deficiency potentiates β-cell regeneration via translational regulation
title_fullStr MNK2 deficiency potentiates β-cell regeneration via translational regulation
title_full_unstemmed MNK2 deficiency potentiates β-cell regeneration via translational regulation
title_short MNK2 deficiency potentiates β-cell regeneration via translational regulation
title_sort mnk2 deficiency potentiates β-cell regeneration via translational regulation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7613404/
https://www.ncbi.nlm.nih.gov/pubmed/35697798
http://dx.doi.org/10.1038/s41589-022-01047-x
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