title: The diabetes susceptibility gene Clec16a regulates mitophagy.
abstract: Clec16a has been identified as a disease susceptibility gene for type 1 diabetes, multiple sclerosis, and adrenal dysfunction, but its function is unknown. Here we report that Clec16a is a membrane-associated endosomal protein that interacts with E3 ubiquitin ligase Nrdp1. Loss of Clec16a leads to an increase in the Nrdp1 target Parkin, a master regulator of mitophagy. Islets from mice with pancreas-specific deletion of Clec16a have abnormal mitochondria with reduced oxygen consumption and ATP concentration, both of which are required for normal β cell function. Indeed, pancreatic Clec16a is required for normal glucose-stimulated insulin release. Moreover, patients harboring a diabetogenic SNP in the Clec16a gene have reduced islet Clec16a expression and reduced insulin secretion. Thus, Clec16a controls β cell function and prevents diabetes by controlling mitophagy. This pathway could be targeted for prevention and control of diabetes and may extend to the pathogenesis of other Clec16a- and Parkin-associated diseases.
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine and the Institute for Diabetes, Obesity and Metabolism of the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Division of Metabolism, Endocrinology & Diabetes and Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48105, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Soleimanpour
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine and the Institute for Diabetes, Obesity and Metabolism of the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Aditi
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Bakay
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine and the Institute for Diabetes, Obesity and Metabolism of the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Alana M
authors.initials: AM
authors.lastname: Ferrari
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine and the Institute for Diabetes, Obesity and Metabolism of the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: David N
authors.initials: DN
authors.lastname: Groff
authors.affiliation: Lund University Diabetes Center, Department of Clinical Sciences, Diabetes & Endocrinology, Skåne University Hospital, Lund University, SE-205 02 Malmö, Sweden.
authors.forename: João
authors.initials: J
authors.lastname: Fadista
authors.affiliation: Children's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USA.
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Spruce
authors.affiliation: McNair Medical Institute, Pediatric Diabetes and Endocrinology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Jake A
authors.initials: JA
authors.lastname: Kushner
authors.affiliation: Lund University Diabetes Center, Department of Clinical Sciences, Diabetes & Endocrinology, Skåne University Hospital, Lund University, SE-205 02 Malmö, Sweden.
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.affiliation: Children's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USA.
authors.forename: Steven H
authors.initials: SH
authors.lastname: Seeholzer
authors.affiliation: Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Brett A
authors.initials: BA
authors.lastname: Kaufman
authors.affiliation: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine and the Institute for Diabetes, Obesity and Metabolism of the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address: stoffers@mail.med.upenn.edu.
authors.forename: Doris A
authors.initials: DA
authors.lastname: Stoffers
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000473:pathology; D020022:Genetic Predisposition to Disease; D005947:Glucose / Q000378:metabolism; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology*; D037181:Lectins, C-Type / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008247:Lysosomes / Q000737:chemistry / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D063306:Mitophagy; D008969:Molecular Sequence Data; D009004:Monosaccharide Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D044767:Ubiquitin-Protein Ligases
chemical_list: C522505:CLEC16A protein, human; C000591253:CLEC16A protein, mouse; D002352:Carrier Proteins; D037181:Lectins, C-Type; D008565:Membrane Proteins; D009004:Monosaccharide Transport Proteins; C435904:Rnf41 protein, mouse; D044767:Ubiquitin-Protein Ligases; D005947:Glucose