2. Academic Validation
  3. MNK2 deficiency potentiates β-cell regeneration via translational regulation

MNK2 deficiency potentiates β-cell regeneration via translational regulation

  • Nat Chem Biol. 2022 Sep;18(9):942-953. doi: 10.1038/s41589-022-01047-x.
Christos Karampelias 1,  Kathleen Watt 2,  Charlotte L Mattsson 1,  Ángel Fernández Ruiz 3 4 5,  Habib Rezanejad 6,  Jiarui Mi 1,  Xiaojing Liu 7 8,  Lianhe Chu 1,  Jason W Locasale 7,  Gregory S Korbutt 6,  Meritxell Rovira 3 4 5,  Ola Larsson 2,  Olov Andersson 9
Affiliations

Affiliations

  • 1 Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
  • 2 Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
  • 3 Department of Physiological Science, School of Medicine, University of Barcelona (UB), L'Hospitalet de Llobregat, Barcelona, Spain.
  • 4 Pancreas Regeneration: Pancreatic Progenitors and Their Niche Group, Regenerative Medicine Program, P-CMR[C], Institut d'Investigació Biomèdica de Bellvitge - IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
  • 5 Center for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain.
  • 6 Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
  • 7 Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA.
  • 8 Department of Molecular and Structural Biochemistry, NC State University, Raleigh, NC, USA.
  • 9 Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden. olov.andersson@ki.se.
PMID: 35697798 DOI: 10.1038/s41589-022-01047-x
Abstract

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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