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Department of Biological Sciences

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https://hdl.handle.net/20.500.14078/6

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Browsing Department of Biological Sciences by Author "Andersson, Olov"

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    MNK2 deficiency potentiates β-cell regeneration via translational regulation
    (2022) Karampelias, Christos; Watt, Kathleen; Mattsson, Charlotte L.; Ruiz, Angel Fernández; Rezanejad, Habib; Mi, Jiarui; Liu, Xiaojing; Chu, Lianhe; Locasale, Jason W.; Korbutt, Gregory S.; Rovira, Meritxell; Larsson, Ola; 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.
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    Reinforcing one-carbon metabolism via folic acid/Folr1 promotes β-cell differentiation
    (2021) Karampelias, Christos; Rezanejad, Habib; Rosko, Mandy; Duan, Likun; Lu, Jing; Pazzagli, Laura; Bertolino, Philippe; Cesta, Carolyn E.; Liu, Xiaojing; Korbutt, Gregory S.; Andersson, Olov
    Diabetes can be caused by an insufficiency in β-cell mass. Here, we performed a genetic screen in a zebrafish model of β-cell loss to identify pathways promoting β-cell regeneration. We found that both folate receptor 1 (folr1) overexpression and treatment with folinic acid, stimulated β-cell differentiation in zebrafish. Treatment with folinic acid also stimulated β-cell differentiation in cultures of neonatal pig islets, showing that the effect could be translated to a mammalian system. In both zebrafish and neonatal pig islets, the increased β-cell differentiation originated from ductal cells. Mechanistically, comparative metabolomic analysis of zebrafish with/without β-cell ablation and with/without folinic acid treatment indicated β-cell regeneration could be attributed to changes in the pyrimidine, carnitine, and serine pathways. Overall, our results suggest evolutionarily conserved and previously unknown roles for folic acid and one-carbon metabolism in the generation of β-cells.