title: PTBP1 is required for glucose-stimulated cap-independent translation of insulin granule proteins and Coxsackieviruses in beta cells.
abstract: Glucose and GLP-1 stimulate not only insulin secretion, but also the post-transcriptional induction of insulin granule biogenesis. This process involves the nucleocytoplasmic translocation of the RNA binding protein PTBP1. Binding of PTBP1 to the 3'-UTRs of mRNAs for insulin and other cargoes of beta cell granules increases their stability. Here we show that glucose enhances also the binding of PTBP1 to the 5'-UTRs of these transcripts, which display IRES activity, and their translation exclusively in a cap-independent fashion. Accordingly, glucose-induced biosynthesis of granule cargoes was unaffected by pharmacological, genetic or Coxsackievirus-mediated inhibition of cap-dependent translation. Infection with Coxsackieviruses, which also depend on PTBP1 for their own cap-independent translation, reduced instead granule stores and insulin release. These findings provide insight into the mechanism for glucose-induction of insulin granule production and on how Coxsackieviruses, which have been implicated in the pathogenesis of type 1 diabetes, can foster beta cell failure.
authors: Paul Langerhans Institute Dresden, TU Dresden Germany ; German Center for Diabetes Research, 01307 Dresden, Germany.
authors: Klaus-Peter
authors: KP
authors: Knoch
authors: Paul Langerhans Institute Dresden, TU Dresden Germany ; German Center for Diabetes Research, 01307 Dresden, Germany.
authors: Suchita
authors: S
authors: Nath-Sain
authors: Paul Langerhans Institute Dresden, TU Dresden Germany ; German Center for Diabetes Research, 01307 Dresden, Germany.
authors: Antje
authors: A
authors: Petzold
authors: Paul Langerhans Institute Dresden, TU Dresden Germany ; German Center for Diabetes Research, 01307 Dresden, Germany.
authors: Hendryk
authors: H
authors: Schneider
authors: Paul Langerhans Institute Dresden, TU Dresden Germany ; German Center for Diabetes Research, 01307 Dresden, Germany.
authors: Mike
authors: M
authors: Beck
authors: Paul Langerhans Institute Dresden, TU Dresden Germany ; German Center for Diabetes Research, 01307 Dresden, Germany.
authors: Carolin
authors: C
authors: Wegbrod
authors: Paul Langerhans Institute Dresden, TU Dresden Germany ; German Center for Diabetes Research, 01307 Dresden, Germany.
authors: Anke
authors: A
authors: Sönmez
authors: Paul Langerhans Institute Dresden, TU Dresden Germany ; German Center for Diabetes Research, 01307 Dresden, Germany.
authors: Carla
authors: C
authors: Münster
authors: Paul Langerhans Institute Dresden, TU Dresden Germany ; German Center for Diabetes Research, 01307 Dresden, Germany.
authors: Anne
authors: A
authors: Friedrich
authors: National Institute for Health and Welfare, Helsinki, Finland.
authors: Merja
authors: M
authors: Roivainen
authors: Paul Langerhans Institute Dresden, TU Dresden Germany ; Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
authors: Michele
authors: M
authors: Solimena
keywords: Beta cells; CV, Coxsackievirus; Diabetes; ER, endoplasmic reticulum; EV, Enterovirus; F, Faulkner; FL, firefly luciferase; IRES, internal ribosomal entry site; ITAF, IRES-trans-acting factor; Insulin; MCA, MIN6 cell adapted; PABP, poly(A)-binding protein; PC, prohormone convertase; PTBP1, polypyrimidine tract-binding protein 1; Polypyrimidine tract-binding protein; S6K1, p70S6 Kinase 1; Secretory granules; T1D, type 1 diabetes; Translation; UTR, untranslated region; Virus; eIF4E-V5, eIF4E tagged at its C-terminus with a V5-epitope; mTORC1, mammalian Target Of Rapamycin Complex 1