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Knoch, K.P.* ; Nath-Sain, S.* ; Petzold, A.* ; Schneider, H.* ; Beck, M.* ; Wegbrod, C.* ; Sönmez, A.* ; Münster, C.* ; Friedrich, A.* ; Roivainen, M.* ; Solimena, M.*

PTBP1 is required for glucose-stimulated cap-independent translation of insulin granule proteins and Coxsackieviruses in beta cells.

Mol. Metab. 3, 518-530 (2014)
Publ. Version/Full Text DOI
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
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, Eif
ISSN (print) / ISBN 2212-8778
e-ISSN 2212-8778
Quellenangaben Volume: 3, Issue: 5, Pages: 518-530 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place Amsterdam
Reviewing status Peer reviewed
Institute(s) Institute for Pancreatic Beta Cell Research (IPI)
German Center for Diabetes Reseach (DZD)