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Wolfram syndrome 1 and adenylyl cyclase 8 interact at the plasma membrane to regulate insulin production and secretion

Nature Cell Biology volume 14, pages 1105–1112 (2012)Cite this article

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A Retraction to this article was published on 23 December 2014

Abstract

Endoplasmic reticulum (ER) stress causes pancreatic β-cell dysfunction and contributes to β-cell loss and the progression of type 2 diabetes1,2. Wolfram syndrome 1 (WFS1) has been shown to be an important regulator of the ER stress signalling pathway3; however, its role in β-cell function remains unclear. Here we provide evidence that WFS1 is essential for glucose- and glucagon-like peptide 1 (GLP-1)-stimulated cyclic AMP production and regulation of insulin biosynthesis and secretion. Stimulation with glucose causes WFS1 translocation from the ER to the plasma membrane, where it forms a complex with adenylyl cyclase 8 (AC8), an essential cAMP-generating enzyme in the β-cell that integrates glucose and GLP-1 signalling4. ER stress and mutant WFS1 inhibit complex formation and activation of AC8, reducing cAMP synthesis and insulin secretion. These findings reveal that an ER-stress-related protein has a distinct role outside the ER regulating both insulin biosynthesis and secretion. The reduction of WFS1 protein on the plasma membrane during ER stress is a contributing factor for β-cell dysfunction and progression of type 2 diabetes.

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Figure 1: WFS1 is required for insulin production, storage and secretion in β-cells.
Figure 2: WFS1 modulates cAMP production.
Figure 3: ER stress leads to cAMP defects in β-cells.
Figure 4: WFS1 forms an active complex with AC8.
Figure 5: WFS1 translocates from the ER to the plasma membrane in a glucose-dependent manner.

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Acknowledgements

We thank M. Hara, Y. Adachi, Y. Murakami, L. Leahy, K. Sargent, B. O’Sullivan-Murphy, J. Hollister-Lock, J. Brown, K. Lipson, D. Ahern-Ridlon and X. Wang, for expert technical support; and C. Fonseca, S. Bonner-Weir and G. Waters for data discussions and comments on the manuscript. This work was supported by grants from the NIH (DK067493, DK016746, P60 DK020579, RR024992 and UL1 TR000448) and JDRF (11-2011-40) to F.U.

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Authors and Affiliations

  1. Cardiovascular and Metabolism Disease Area, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA

    Sonya G. Fonseca, Jesper Gromada & Mark Burcin

  2. Division of Endocrinology, Department of Medicine, Metabolism, and Lipid Research, Washington University School of Medicine, St Louis, Missouri 63110, USA

    Fumihiko Urano

  3. Islet Biology and Regenerative Medicine, Joslin Diabetes Center, Boston, Massachusetts 02215, USA

    Gordon C. Weir

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  1. Sonya G. Fonseca
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Contributions

S.F., J.G. and M.B. wrote the manuscript and together with F.U. and G.C.W. conceived the experiments. S.F. carried out most of the experimental work. M.B. and J.G. directed the research programme.

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Correspondence to Sonya G. Fonseca.

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Fonseca, S., Urano, F., Weir, G. et al. Wolfram syndrome 1 and adenylyl cyclase 8 interact at the plasma membrane to regulate insulin production and secretion. Nat Cell Biol 14, 1105–1112 (2012). https://doi.org/10.1038/ncb2578

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