Research ArticlePhysiology

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

See allHide authors and affiliations

Science Signaling  03 Dec 2019:
Vol. 12, Issue 610, eaax0715
DOI: 10.1126/scisignal.aax0715

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Translating into a bigger pancreas

The evolutionarily conserved mRNA translation factor eIF5A is critical for cell proliferation in developmental and oncogenic contexts, and its activity depends on hypusination, a posttranslational modification that is unique to eIF5A. Levasseur et al. found that eIF5A hypusination was critical for postnatal expansion of β cell mass in the pancreas. Mice that could not perform hypusination in β cells did not produce sufficient cyclin D2 to sustain cell cycling and developed diabetes in response to diet-induced obesity. Thus, eIF5A hypusination links increased insulin demand caused by insulin resistance with β cell proliferation to maintain glucose homeostasis.

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.

View Full Text