Hypusine biosynthesis in β cells links polyamine metabolism to facultative cellular proliferation to maintain glucose homeostasis
Authors: Adolfo Garcia-Ocaña
Teresa L Mastracci
Yunlong Liu
Bernhard Maier
Sarah A Tersey
Kara S Orr
Annie R Piñeros
Esther M Levasseur
Laura C Alonso
Raghavendra G Mirmira
Donald Scott
Wenting Wu
Ernesto Bernal-Mizrachi
Emily Anderson-Baucum
Farooq Syed
Amber L Mosley
Kentaro Yamada
Journal: Science Signaling (2019)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Deoxyhypusine synthase; DHPS; mRNA translation; eIF5A; oncogenesis
Affiliations: Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Indiana Biosciences Research Institute, Indianapolis, IN 46202, USA., Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Department of Medicine, University of Miami, Miami, FL 33146, USA., Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA., Diabetes, Obesity, and Metabolism Institute and the Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202, USA. .

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. 

Retracted: No

PubPeer comments:
 Authors claim that they determined the effect of Harmine on proliferation in DHPS inhibited (Gc7-treated) human beta cells (Fig. 6D). However, the data shown in Fig S4 and method provided for measuring cell proliferation by flow cytometric analysis of dispersed human islet cells stained with phospho-Histone H3 (pS28) shows that they did not co-stained the cells with insulin to mark the beta cells. Since Harmine is well-known for non-selective induction of cell proliferation, co-staining the dispersed islet cells for insulin and phospho-Histone H3 (pS28) was necessary to determine effect of these drugs on beta cell proliferation. ![file] , 
 #1 The figure indicates percent pHH3+ INS (insulin)+ cells , 
 Yes, authors have written u201c% Phosphou2013histone H3+ INS+ cellsu201d. But their flow cytometry results shown in Supplementary figure S4 shows Phosphou2013histone H3 (S28) positive cell population was gated. To claim u201c% Phosphou2013histone H3+ INS+ cellsu201d, which would be % proliferating beta cells, authors should show the flow cytometry data gated for Insulin and Phosphou2013histone H3 (S28) co-positive cells. Also, basal rate of proliferation in human beta cells is almost always less than 0.1%. However, the very high (0.23, 0.73, 3.49, 2.32) level basal (vehicle treated) rate of proliferation authors shows that they did not measure proliferation exclusively in beta cells. eIF5A is a ubiquitously expressed protein. Why the micrographs for eIF5AHyp and eIF5A Total immunostaining shown in Fig. 3 and Fig.5 shows the immunostaining only in islets and not in other (exocrine) pancreatic cells as if eIF5A is a beta cell-specific protein and its hypusination happens only in beta cells? How the authors confirmed the specificity of these immunostainings? ,