MassIVE MSV000093089

Partial Public PXD046093

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

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Description

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. [doi:10.25345/C5794149V] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: beta cell maturation ; mRNA translation ; translational regulation ; beta cell development ; beta cell identity ; beta cell function ; diabetes

Contact

Principal Investigators:
(in alphabetical order) 		Amber L. Mosley, Indiana University School of Medicine, USA
Teresa Mastracci, Indiana University-Purdue University-Indianapolis, USA
Submitting User: edoud

Publications

Connors CT, Anderson-Baucum EK, Rosario S, Villaca CBP, Rutan CD, Childress PJ, Padgett LR, Robertson MA, Mastracci TL.
Deoxyhypusine synthase is required for the translational regulation of pancreatic beta cell maturation.
bioRxiv. Epub 2023 Apr 24.

Connors CT, Villaca CBP, Anderson-Baucum EK, Rosario SR, Rutan CD, Childress PJ, Padgett LR, Robertson MA, Mastracci TL.
A Translational Regulatory Mechanism Mediated by Hypusinated Eukaryotic Initiation Factor 5A Facilitates ?-Cell Identity and Function.
Diabetes. 2024 Mar 1;73(3):461-473.

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