Elsevier

Molecular Metabolism

Volume 3, Issue 5, August 2014, Pages 518-530
Molecular Metabolism

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

https://doi.org/10.1016/j.molmet.2014.05.002Get rights and content
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open access

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.

Keywords

Beta cells
Diabetes
Insulin
Polypyrimidine tract-binding protein
Secretory granules
Translation
Virus

Abbreviations

CV
Coxsackievirus
eIF4E-V5
eIF4E tagged at its C-terminus with a V5-epitope
ER
endoplasmic reticulum
EV
Enterovirus
F
Faulkner
FL
firefly luciferase
IRES
internal ribosomal entry site
ITAF
IRES-trans-acting factor
mTORC1
mammalian Target Of Rapamycin Complex 1
MCA
MIN6 cell adapted
PABP
poly(A)-binding protein
PC
prohormone convertase
PTBP1
polypyrimidine tract-binding protein 1
S6K1
p70S6 Kinase 1
T1D
type 1 diabetes
UTR
untranslated region

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