Neuron-enriched RNA-binding Proteins Regulate Pancreatic Beta Cell Function and Survival

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Neuron-enriched RNA-binding Proteins Regulate Pancreatic Beta Cell Function and Survival. / Juan-Mateu, Jon Agraves; Rech, Tatiana H; Villate, Olatz; Lizarraga-Mollinedo, Esther; Wendt, Anna; Turatsinze, Jean-Valery; Brondani, Leticia A; Nardelli, Tarlliza R; Nogueira, Tatiane C; Esguerra, Jonathan; Alvelos, Maria In Ecircs; Marchetti, Piero; Eliasson, Lena; Eizirik, D Eacutecio L.

In: Journal of Biological Chemistry, Vol. 292, No. 8, 2017, p. 3466-3480.

Research output: Contribution to journalArticle

Harvard

Juan-Mateu, JA, Rech, TH, Villate, O, Lizarraga-Mollinedo, E, Wendt, A, Turatsinze, J-V, Brondani, LA, Nardelli, TR, Nogueira, TC, Esguerra, J, Alvelos, MIE, Marchetti, P, Eliasson, L & Eizirik, DEL 2017, 'Neuron-enriched RNA-binding Proteins Regulate Pancreatic Beta Cell Function and Survival', Journal of Biological Chemistry, vol. 292, no. 8, pp. 3466-3480. https://doi.org/10.1074/jbc.M116.748335

APA

Juan-Mateu, J. A., Rech, T. H., Villate, O., Lizarraga-Mollinedo, E., Wendt, A., Turatsinze, J-V., Brondani, L. A., Nardelli, T. R., Nogueira, T. C., Esguerra, J., Alvelos, M. I. E., Marchetti, P., Eliasson, L., & Eizirik, D. E. L. (2017). Neuron-enriched RNA-binding Proteins Regulate Pancreatic Beta Cell Function and Survival. Journal of Biological Chemistry, 292(8), 3466-3480. https://doi.org/10.1074/jbc.M116.748335

CBE

Juan-Mateu JA, Rech TH, Villate O, Lizarraga-Mollinedo E, Wendt A, Turatsinze J-V, Brondani LA, Nardelli TR, Nogueira TC, Esguerra J, Alvelos MIE, Marchetti P, Eliasson L, Eizirik DEL. 2017. Neuron-enriched RNA-binding Proteins Regulate Pancreatic Beta Cell Function and Survival. Journal of Biological Chemistry. 292(8):3466-3480. https://doi.org/10.1074/jbc.M116.748335

MLA

Vancouver

Author

Juan-Mateu, Jon Agraves ; Rech, Tatiana H ; Villate, Olatz ; Lizarraga-Mollinedo, Esther ; Wendt, Anna ; Turatsinze, Jean-Valery ; Brondani, Leticia A ; Nardelli, Tarlliza R ; Nogueira, Tatiane C ; Esguerra, Jonathan ; Alvelos, Maria In Ecircs ; Marchetti, Piero ; Eliasson, Lena ; Eizirik, D Eacutecio L. / Neuron-enriched RNA-binding Proteins Regulate Pancreatic Beta Cell Function and Survival. In: Journal of Biological Chemistry. 2017 ; Vol. 292, No. 8. pp. 3466-3480.

RIS

TY - JOUR

T1 - Neuron-enriched RNA-binding Proteins Regulate Pancreatic Beta Cell Function and Survival

AU - Juan-Mateu, Jon Agraves

AU - Rech, Tatiana H

AU - Villate, Olatz

AU - Lizarraga-Mollinedo, Esther

AU - Wendt, Anna

AU - Turatsinze, Jean-Valery

AU - Brondani, Leticia A

AU - Nardelli, Tarlliza R

AU - Nogueira, Tatiane C

AU - Esguerra, Jonathan

AU - Alvelos, Maria In Ecircs

AU - Marchetti, Piero

AU - Eliasson, Lena

AU - Eizirik, D Eacutecio L

N1 - Copyright © 2017, The American Society for Biochemistry and Molecular Biology.

PY - 2017

Y1 - 2017

N2 - Pancreatic beta cell failure is the central event leading to diabetes. Beta cells share many phenotypic traits with neurons, and proper beta cell function relies on the activation of several neuronal-like transcription programs. Regulation of gene expression by alternative splicing plays a pivotal role in brain, where it affects neuronal development, function and disease. The role of alternative splicing in beta cells remains unclear, but recent data indicate that splicing alterations modulated by both inflammation and susceptibility genes for diabetes contribute to beta cell dysfunction and death. Here we used RNA sequencing to compare the expression of splicing-regulatory RNA-binding proteins in human islets, brain and other human tissues, and identified a cluster of splicing regulators that are expressed in both beta cells and brain. Four of them, namely Elavl4, Nova2, Rbox1 and Rbfox2 were selected for subsequent functional studies in insulin-producing rat INS-1E, human EndoC-βH1 cells, and in primary rat beta cells. Silencing of Elavl4 and Nova2 increased beta cell apoptosis, while silencing of Rbfox1 and Rbfox2 increased insulin content and secretion. Interestingly, Rbfox1 silencing modulates the splicing of the actin-remodeling protein gelsolin, increasing gelsolin expression and leading to faster glucose-induced actin depolymerization and increased insulin release. Taken together, these findings indicate that beta cells share common splicing regulators and programs with neurons. These splicing regulators play key roles in insulin release and beta cell survival and their dysfunction may contribute to the loss of functional beta cell mass in diabetes.

AB - Pancreatic beta cell failure is the central event leading to diabetes. Beta cells share many phenotypic traits with neurons, and proper beta cell function relies on the activation of several neuronal-like transcription programs. Regulation of gene expression by alternative splicing plays a pivotal role in brain, where it affects neuronal development, function and disease. The role of alternative splicing in beta cells remains unclear, but recent data indicate that splicing alterations modulated by both inflammation and susceptibility genes for diabetes contribute to beta cell dysfunction and death. Here we used RNA sequencing to compare the expression of splicing-regulatory RNA-binding proteins in human islets, brain and other human tissues, and identified a cluster of splicing regulators that are expressed in both beta cells and brain. Four of them, namely Elavl4, Nova2, Rbox1 and Rbfox2 were selected for subsequent functional studies in insulin-producing rat INS-1E, human EndoC-βH1 cells, and in primary rat beta cells. Silencing of Elavl4 and Nova2 increased beta cell apoptosis, while silencing of Rbfox1 and Rbfox2 increased insulin content and secretion. Interestingly, Rbfox1 silencing modulates the splicing of the actin-remodeling protein gelsolin, increasing gelsolin expression and leading to faster glucose-induced actin depolymerization and increased insulin release. Taken together, these findings indicate that beta cells share common splicing regulators and programs with neurons. These splicing regulators play key roles in insulin release and beta cell survival and their dysfunction may contribute to the loss of functional beta cell mass in diabetes.

U2 - 10.1074/jbc.M116.748335

DO - 10.1074/jbc.M116.748335

M3 - Article

C2 - 28077579

VL - 292

SP - 3466

EP - 3480

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 1083-351X

IS - 8

ER -