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A translational regulatory mechanism mediated by hypusinated eukaryotic initiation factor 5A facilitates beta cell identity and function

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posted on 2023-12-06, 20:43 authored by Craig T. Connors, Catharina B.P. Villaca, Emily K. Anderson-Baucum, Spencer R. Rosario, Caleb D. Rutan, Paul J. Childress, Leah R. Padgett, Morgan A. Robertson, Teresa L. Mastracci

As professional secretory cells, beta 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 beta 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 beta 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 beta cell identity and function. The mRNA translation function of eIF5A is only active when it is post-translationally modified (“hypusinated”) by the enzyme deoxyhypusine synthase (DHPS). We have discovered that the absence of beta cell DHPS in mice reduces the synthesis of proteins critical to beta cell identity and function at the stage of beta 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 beta cell, a metabolically responsive secretory cell, to maintain the integrity of protein synthesis necessary during times of induced or increased demand.

Funding

This work was supported by funding to TLM from the Juvenile Diabetes Research Foundation (JDRF) (5-CDA-2016-194-A-N) and the National Institutes of Health (NIH) (R01DK121987), and funding to SRR from the NIH–IOTN: Data Management and Resource-Sharing Center (U24CA232979). The mass spectrometry work performed by the Indiana University School of Medicine Center for Proteome Analysis. Acquisition of the IUSM Proteomics instrumentation was provided by the Indiana University Precision Health Initiative. The proteomics work was supported, in part, by the Indiana Clinical and Translational Sciences Institute funded in part by funds (UL1TR002529) from the NIH, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award, and the Cancer Center Support Grant for the IU Simon Comprehensive Cancer Center (P30CA082709) from the National Cancer Institute.

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