The effect Echovirus 9 on posttranscriptional mechanism in human beta cells EndoCßH1 cells

 

The reason for preferential autoimmunity towards insulin, ICA512/IA-2 and other cargoes of beta cell secretory granules in type 1 diabetes (T1D) remains unknown. We have shown that glucose stimulation of beta cells rapidly and selectively up-regulates the Polypyrimidine tract binding protein 1 (PTBP1) -dependent cap-independent translation of granule precursor cargoes, including proinsulin, proICA512/IA-2, prochromogranin A and hormone convertases proPC1/3 and proPC2 [Knoch, K.-P. et al. 2014]. PTBP1-dependent cap-independent translation is also required for replication of Enteroviruses (Evs) in beta cells potentially triggering or accelerating T1D onset, such as Coxsackieviruses B or Echoviruses.

Since PTBP1 is a key proteins for regulation of insulin granule biosynthesis and viral translation, it is important to understand better the molecular events following virus infection. Therefore, the aim of this project is to investigate if and how Echovirus 9 (EV-9) affects PTBP1 and thereby the traffic and stability of granule cargoes.

Infection of human beta cell line EndoCßH1 with EV-9 leads to a strong reduction of the insulin content without changed mRNA levels. In paralell we observe a complete redistribution of PTBP1 from the nuceus to the cytosol, meaning that the levels of key regulator of insulin translation are increased. Nuclear exclusion of PTBP1 upon EV-9 infection correlate with reduced levels of the nuclear pore proteins 62 and 98. Taken together, our data indicate that EV-9 reduces granule stores while impairinng nucleocytosolic transport. The impact of these changes on antigen presentation of beta cells is being investigated further.