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Proc Natl Acad Sci U S A. 2019 Oct 1;116(40):19983-19988. doi: 10.1073/pnas.1903678116. Epub 2019 Sep 16.

Atp6ap2 deletion causes extensive vacuolation that consumes the insulin content of pancreatic β cells.

Author information

1
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Sciences, La Trobe University, Bundoora, VIC 3086, Australia; k.binger@latrobe.edu.au.
2
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC 3010, Australia.
3
Molecular Diabetology, Paul Langerhans Institute Dresden (PLID) of the Helmholtz German Center for Diabetes Research (DZD e.V.) Munich, University Hospital Carl Gustav Carus and Faculty of Medicine, TU Dresden, 01307 Dresden, Germany.
4
Department of Genetics, Harvard Medical School, Boston, MA 02115.
5
Cardiovascular and Metabolic Diseases, Max Delbruck Center (MDC) for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany.
6
Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin and Max Delbruck Center for Molecular Medicine, 13125 Berlin, Germany.
7
Cellular Imaging Facility, Leibniz Institute for Molecular Pharmacology (FMP) Berlin, 13125 Berlin, Germany.
8
Center for Molecular and Cellular Bioengineering, Center for Regenerative Therapies Dresden, TU Dresden, 01307 Dresden, Germany.
9
Center for Interdisciplinary Research in Biology, UMR INSERM U1050/CNRS 7241, Collège de France, 75231 Paris, France.
10
Institute for Fundamental Biomedical Research, All Children's Hospital, Johns Hopkins University, St. Petersburg, FL 33701.
11
Department of Diabetology Endocrinology and Nephrology, University Hospital Tübingen, Eberhard Karls University Tübingen, 72074 Tübingen, Germany.
12
Department of Therapy of Diabetes, Institute of Diabetes Research and Metabolic Diseases in the Helmholtz Center Munich, Eberhard Karls University Tübingen, 72074 Tübingen, Germany.
13
Division of Diabetes and Nutritional Sciences, Rayne Institute, King's College London, London SE5 9RJ, United Kingdom.

Abstract

Pancreatic β cells store insulin within secretory granules which undergo exocytosis upon elevation of blood glucose levels. Crinophagy and autophagy are instead responsible to deliver damaged or old granules to acidic lysosomes for intracellular degradation. However, excessive consumption of insulin granules can impair β cell function and cause diabetes. Atp6ap2 is an essential accessory component of the vacuolar ATPase required for lysosomal degradative functions and autophagy. Here, we show that Cre recombinase-mediated conditional deletion of Atp6ap2 in mouse β cells causes a dramatic accumulation of large, multigranular vacuoles in the cytoplasm, with reduction of insulin content and compromised glucose homeostasis. Loss of insulin stores and gigantic vacuoles were also observed in cultured insulinoma INS-1 cells upon CRISPR/Cas9-mediated removal of Atp6ap2. Remarkably, these phenotypic alterations could not be attributed to a deficiency in autophagy or acidification of lysosomes. Together, these data indicate that Atp6ap2 is critical for regulating the stored insulin pool and that a balanced regulation of granule turnover is key to maintaining β cell function and diabetes prevention.

KEYWORDS:

(pro)renin receptor; autophagy; diabetes; vacuolar H+ ATPase

PMID:
31527264
DOI:
10.1073/pnas.1903678116

Conflict of interest statement

The authors declare no conflict of interest.

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