Hypusine biosynthesis in β cells links polyamine metabolism to facultative cellular proliferation to maintain glucose homeostasis

Esther M. Levasseur, Kentaro Yamada, Annie R. Piñeros, Wenting Wu, Farooq Syed, Kara S. Orr, Emily Anderson-Baucum, Teresa L. Mastracci, Bernhard Maier, Amber L. Mosley, Yunlong Liu, Ernesto Bernal-Mizrachi, Laura C. Alonso, Donald Scott, Adolfo Garcia-Ocaña, Sarah A. Tersey, Raghavendra G. Mirmira

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Deoxyhypusine synthase (DHPS) uses the polyamine spermidine to catalyze the hypusine modification of the mRNA translation factor eIF5A and promotes oncogenesis through poorly defined mechanisms. Because germline deletion of Dhps is embryonically lethal, its role in normal postnatal cellular function in vivo remains unknown. We generated a mouse model that enabled the inducible, postnatal deletion of Dhps specifically in postnatal islet β cells, which function to maintain glucose homeostasis. Removal of Dhps did not have an effect under normal physiologic conditions. However, upon development of insulin resistance, which induces β cell proliferation, Dhps deletion caused alterations in proteins required for mRNA translation and protein secretion, reduced production of the cell cycle molecule cyclin D2, impaired β cell proliferation, and induced overt diabetes. We found that hypusine biosynthesis was downstream of protein kinase C-ζ and was required for c-Myc–induced proliferation. Our studies reveal a requirement for DHPS in β cells to link polyamines to mRNA translation to effect facultative cellular proliferation and glucose homeostasis.

Original languageEnglish (US)
Article numbereaax0715
JournalScience Signaling
Volume12
Issue number610
DOIs
StatePublished - Dec 3 2019

    Fingerprint

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Levasseur, E. M., Yamada, K., Piñeros, A. R., Wu, W., Syed, F., Orr, K. S., Anderson-Baucum, E., Mastracci, T. L., Maier, B., Mosley, A. L., Liu, Y., Bernal-Mizrachi, E., Alonso, L. C., Scott, D., Garcia-Ocaña, A., Tersey, S. A., & Mirmira, R. G. (2019). Hypusine biosynthesis in β cells links polyamine metabolism to facultative cellular proliferation to maintain glucose homeostasis. Science Signaling, 12(610), [eaax0715]. https://doi.org/10.1126/scisignal.aax0715