Cell. 2015 Dec 3;163(6):1457-67. doi: 10.1016/j.cell.2015.10.076. Epub 2015 Nov 25.
β-Cell Insulin Secretion Requires the Ubiquitin Ligase COP1.
Suriben R1, Kaihara KA2, Paolino M1, Reichelt M3, Kummerfeld SK4, Modrusan Z5, Dugger DL1, Newton K1, Sagolla M3, Webster JD3, Liu J4, Hebrok M2, Dixit VM6.
Abstract
A
variety of signals finely tune insulin secretion by pancreatic β cells
to prevent both hyper-and hypoglycemic states. Here, we show that
post-translational regulation of the transcription factors ETV1, ETV4,
and ETV5 by the ubiquitin ligase COP1 (also called RFWD2)
in β cells is critical for insulin secretion. Mice lacking COP1 in β
cells developed diabetes due to insulin granule docking defects that
were fully rescued by genetic deletion of Etv1, Etv4, and Etv5. Genes
regulated by ETV1, ETV4, or ETV5 in the absence of mouse COP1 were
enriched in human diabetes-associated genes, suggesting that they also
influence human β-cell pathophysiology. In normal β cells, ETV4 was
stabilized upon membrane depolarization and limited insulin secretion
under hyperglycemic conditions. Collectively, our data reveal that ETVs
negatively regulate insulin secretion for the maintenance of
normoglycemia.
Copyright © 2015 Elsevier Inc. All rights reserved.
Comment in
- Metabolism: Keeping insulin secretion in check. [Nat Rev Mol Cell Biol. 2016]
- PMID:
- 26627735
- DOI:
- 10.1016/j.cell.2015.10.076
- [Indexed for MEDLINE]
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