GSE200477
Polysome profiling quantified by RNA sequencing in PANC1 cells treated with MNK2 inhibitors or DMSO
Regenerating pancreatic b-cells is a potential curative approach for diabetes. We previously identified the small molecule CID661578 as a potent inducer of b-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 that was genetically validated in vivo. CID661578 increased b-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. This blocking activity augmented the interaction between EIF4E and EIF4G, which is necessary for both hypertranslation and b-cell regeneration. Taken together, our findings demonstrate a targetable role of MNK2-controlled translation in b-cell regeneration, a role that warrants further investigation in diabetes. Overall design: Four replicated of polysome profiling were performed on PANC1 cells treated with MNK2 inhibitors (CID661578 [40uM], and cercosporamide [5uM]) or DMSO for 6 hours. Total cytosolic RNA, and polysome-associated mRNA (mRNA associated with > 3 ribosomes) were quantified using RNA sequencing.