PTBP1 is Required for Glucose-stimulated Cap-independent Translation of Insulin Granule Proteins and Coxsackieviruses in Beta Cells

Overview

Journal Mol Metab

Specialty Cell Biology

Date 2014 Jul 26

PMID 25061557

Citations 25

Authors

Klaus-Peter Knoch

Suchita Nath-Sain

Antje Petzold

Hendryk Schneider

Mike Beck

Carolin Wegbrod

Anke Sonmez

Carla Munster

Anne Friedrich

Merja Roivainen

Michele Solimena

Affiliations

Soon will be listed here.

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.

Citing Articles

Small Molecule with Big Impact: Metarrestin Targets the Perinucleolar Compartment in Cancer Metastasis.

Kashyap V, Sharma B, Pandey D, Singh A, Peasah-Darkwah G, Singh B Cells. 2025; 13(24.

PMID: 39768145 PMC: 11674295. DOI: 10.3390/cells13242053.

PTBP1 as a potential regulator of disease.

Yu Q, Wu T, Xu W, Wei J, Zhao A, Wang M Mol Cell Biochem. 2023; 479(11):2875-2894.

PMID: 38129625 DOI: 10.1007/s11010-023-04905-x.

Mutated lncRNA increase the risk of type 2 diabetes by promoting β cell dysfunction and insulin resistance.

Guo W, Guo Q, Liu Y, Yan D, Jin L, Zhang R Cell Death Dis. 2022; 13(10):904.

PMID: 36302749 PMC: 9613878. DOI: 10.1038/s41419-022-05348-w.

Post-transcriptional control by RNA-binding proteins in diabetes and its related complications.

Zhang S, Yang X, Jiang M, Ma L, Hu J, Zhang H Front Physiol. 2022; 13:953880.

PMID: 36277184 PMC: 9582753. DOI: 10.3389/fphys.2022.953880.

Persistent coxsackievirus B infection and pathogenesis of type 1 diabetes mellitus.

Nekoua M, Alidjinou E, Hober D Nat Rev Endocrinol. 2022; 18(8):503-516.

PMID: 35650334 PMC: 9157043. DOI: 10.1038/s41574-022-00688-1.

References

Dotta F, Censini S, van Halteren A, Marselli L, Masini M, Dionisi S . Coxsackie B4 virus infection of beta cells and natural killer cell insulitis in recent-onset type 1 diabetic patients. Proc Natl Acad Sci U S A. 2007; 104(12):5115-20. PMC: 1829272. DOI: 10.1073/pnas.0700442104. View

Kafasla P, Morgner N, Poyry T, Curry S, Robinson C, Jackson R . Polypyrimidine tract binding protein stabilizes the encephalomyocarditis virus IRES structure via binding multiple sites in a unique orientation. Mol Cell. 2009; 34(5):556-68. DOI: 10.1016/j.molcel.2009.04.015. View

Kafasla P, Mickleburgh I, Llorian M, Coelho M, Gooding C, Cherny D . Defining the roles and interactions of PTB. Biochem Soc Trans. 2012; 40(4):815-20. DOI: 10.1042/BST20120044. View

Gotoh M, Maki T, Kiyoizumi T, Satomi S, Monaco A . An improved method for isolation of mouse pancreatic islets. Transplantation. 1985; 40(4):437-8. DOI: 10.1097/00007890-198510000-00018. View

Fred R, Welsh N . The importance of RNA binding proteins in preproinsulin mRNA stability. Mol Cell Endocrinol. 2008; 297(1-2):28-33. DOI: 10.1016/j.mce.2008.06.007. View

Ivanova A, Kalaidzidis Y, Dirkx R, Sarov M, Gerlach M, Schroth-Diez B . Age-dependent labeling and imaging of insulin secretory granules. Diabetes. 2013; 62(11):3687-96. PMC: 3806613. DOI: 10.2337/db12-1819. View

Vagner S, Galy B, Pyronnet S . Irresistible IRES. Attracting the translation machinery to internal ribosome entry sites. EMBO Rep. 2001; 2(10):893-8. PMC: 1084086. DOI: 10.1093/embo-reports/kve208. View

Verma B, Bhattacharyya S, Das S . Polypyrimidine tract-binding protein interacts with coxsackievirus B3 RNA and influences its translation. J Gen Virol. 2010; 91(Pt 5):1245-55. DOI: 10.1099/vir.0.018507-0. View

Halban P . Differential rates of release of newly synthesized and of stored insulin from pancreatic islets. Endocrinology. 1982; 110(4):1183-8. DOI: 10.1210/endo-110-4-1183. View

10.

Tillmar L, Carlsson C, Welsh N . Control of insulin mRNA stability in rat pancreatic islets. Regulatory role of a 3'-untranslated region pyrimidine-rich sequence. J Biol Chem. 2001; 277(2):1099-106. DOI: 10.1074/jbc.M108340200. View

11.

Knoch K, Bergert H, Borgonovo B, Saeger H, Altkruger A, Verkade P . Polypyrimidine tract-binding protein promotes insulin secretory granule biogenesis. Nat Cell Biol. 2004; 6(3):207-14. DOI: 10.1038/ncb1099. View

12.

Grieco F, Sebastiani G, Spagnuolo I, Patti A, Dotta F . Immunology in the clinic review series; focus on type 1 diabetes and viruses: how viral infections modulate beta cell function. Clin Exp Immunol. 2012; 168(1):24-9. PMC: 3390489. DOI: 10.1111/j.1365-2249.2011.04556.x. View

13.

Solimena M . Vesicular autoantigens of type 1 diabetes. Diabetes Metab Rev. 1998; 14(3):227-40. DOI: 10.1002/(sici)1099-0895(1998090)14:3<227::aid-dmr215>3.0.co;2-e. View

14.

Lou H, Helfman D, Gagel R, Berget S . Polypyrimidine tract-binding protein positively regulates inclusion of an alternative 3'-terminal exon. Mol Cell Biol. 1998; 19(1):78-85. PMC: 83867. DOI: 10.1128/MCB.19.1.78. View

15.

Seewaldt S, Thomas H, Ejrnaes M, Christen U, Wolfe T, Rodrigo E . Virus-induced autoimmune diabetes: most beta-cells die through inflammatory cytokines and not perforin from autoreactive (anti-viral) cytotoxic T-lymphocytes. Diabetes. 2000; 49(11):1801-9. DOI: 10.2337/diabetes.49.11.1801. View

16.

Garcia-Blanco M, Jamison S, Sharp P . Identification and purification of a 62,000-dalton protein that binds specifically to the polypyrimidine tract of introns. Genes Dev. 1989; 3(12A):1874-86. DOI: 10.1101/gad.3.12a.1874. View

17.

Gilbert W . Alternative ways to think about cellular internal ribosome entry. J Biol Chem. 2010; 285(38):29033-8. PMC: 2937932. DOI: 10.1074/jbc.R110.150532. View

18.

Mziaut H, Trajkovski M, Kersting S, Ehninger A, Altkruger A, Lemaitre R . Synergy of glucose and growth hormone signalling in islet cells through ICA512 and STAT5. Nat Cell Biol. 2006; 8(5):435-45. DOI: 10.1038/ncb1395. View

19.

Clerte C, Hall K . The domains of polypyrimidine tract binding protein have distinct RNA structural preferences. Biochemistry. 2009; 48(10):2063-74. PMC: 2766422. DOI: 10.1021/bi8016872. View

20.

Stoneley M, Willis A . Cellular internal ribosome entry segments: structures, trans-acting factors and regulation of gene expression. Oncogene. 2004; 23(18):3200-7. DOI: 10.1038/sj.onc.1207551. View