As professional secretory cells, β-cells require adaptable mRNA translation to facilitate a rapid synthesis of proteins, including insulin, in response to changing metabolic cues. Specialized mRNA translation programs are essential drivers of cellular development and differentiation. However, in the pancreatic β-cell, the majority of factors identified to promote growth and development function primarily at the level of transcription. Therefore, despite its importance, the regulatory role of mRNA translation in the formation and maintenance of functional β-cells is not well defined. In this study, we have identified a translational regulatory mechanism mediated by the specialized mRNA translation factor eukaryotic initiation factor 5A (eIF5A), which facilitates the maintenance of β-cell identity and function. The mRNA translation function of eIF5A is only active when it is posttranslationally modified (“hypusinated”) by the enzyme deoxyhypusine synthase (DHPS). We have discovered that the absence of β-cell DHPS in mice reduces the synthesis of proteins critical to β-cell identity and function at the stage of β-cell maturation, leading to a rapid and reproducible onset of diabetes. Therefore, our work has revealed a gatekeeper of specialized mRNA translation that permits the β-cell, a metabolically responsive secretory cell, to maintain the integrity of protein synthesis necessary during times of induced or increased demand.

Article Highlights
  • β-Cells are secretory cells that require adaptable mRNA translation for the synthesis of proteins in response to metabolic cues. Our previous work showed that the hypusinated form of the mRNA translation factor eukaryotic initiation factor 5A (eIF5AHYP) translationally regulates acinar cell growth/function. We hypothesized this may also occur in β-cells.

  • We discovered that Ins1, Slc2a2 (Glut2), Ucn3, and Chga are translationally regulated by eIF5AHYP during β-cell maturation. Without deoxyhypusine synthase (DHPS)/eIF5AHYP, β-cells lose identity/function and diabetes ensues.

  • Our findings suggest that secretory cells regulate translation during times of stress. We propose that stimulating translation in the β-cell might reverse defects that contribute to diabetes progression.

This article contains supplementary material online at https://doi.org/10.2337/figshare.24721620.

C.T.C. and C.B.P.V. contributed equally to this work.

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