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MNK2 deficiency potentiates β-cell regeneration via translational regulation.

Nature chemical biology (2022-06-14)
Christos Karampelias, Kathleen Watt, Charlotte L Mattsson, Ángel Fernández Ruiz, Habib Rezanejad, Jiarui Mi, Xiaojing Liu, Lianhe Chu, Jason W Locasale, Gregory S Korbutt, Meritxell Rovira, Ola Larsson, Olov Andersson
RÉSUMÉ

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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Sigma-Aldrich
Anticorps monoclonal ANTI-FLAG® M2 antibody produced in mouse, clone M2, purified immunoglobulin (Purified IgG1 subclass), buffered aqueous solution (10 mM sodium phosphate, 150 mM NaCl, pH 7.4, containing 0.02% sodium azide)
Sigma-Aldrich
Anticorps monoclonal anti-β-actine antibody produced in mouse, clone AC-15, ascites fluid
Sigma-Aldrich
Anti-MKNK2 antibody produced in rabbit, affinity isolated antibody