Glucose-Induced Nuclear Shuttling of ChREBP Is Mediated by Sorcin and Ca2+ Ions in Pancreatic β-Cells

  1. Isabelle Leclerc
  1. Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, Imperial College London, London, U.K
  1. Corresponding authors: Guy A. Rutter, g.rutter@imperial.ac.uk, and Isabelle Leclerc, i.leclerc{at}imperial.ac.uk.
  1. N.A.N. and G.M. contributed equally to this study.

Abstract

Carbohydrate-responsive element-binding protein (ChREBP) is a regulator of pancreatic β-cell gene expression and an important mediator of glucotoxicity. Glucose increases the activity and nuclear localization of ChREBP by still ill-defined mechanisms. Here we reveal, using both MIN6 and primary mouse β-cells, a unique mechanism behind ChREBP nuclear translocation. At low glucose concentrations, ChREBP interacts with sorcin, a penta EF hand Ca2+ binding protein, and is sequestered in the cytosol. Sorcin overexpression inhibits ChREBP nuclear accumulation at high glucose and reduced the activity of L-type pyruvate kinase (L-PK) and TxNIP promoters, two well-characterized ChREBP target genes. Sorcin inactivation by RNA interference increases ChREBP nuclear localization and in vivo binding to the L-PK promoter at low glucose concentrations. Ca2+ influx was essential for this process since Ca2+ chelation with EGTA, or pharmacological inhibition with diazoxide and nifedipine, blocked the effects of glucose. Conversely, mobilization of intracellular Ca2+ with ATP caused the nuclear accumulation of ChREBP. Finally, sorcin silencing inhibited ATP-induced increases in intracellular Ca2+ and glucose-stimulated insulin secretion. We therefore conclude that sorcin retains ChREBP in the cytosol at low glucose concentrations and may act as a Ca2+ sensor for glucose-induced nuclear translocation and the activation of ChREBP-dependent genes.

Footnotes

  • Received September 17, 2010.
  • Accepted November 21, 2011.

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  1. Diabetes vol. 61 no. 3 574-585
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