Publication in detail

Cell 2014 Jun 19;157(7):1577-90. doi: 10.1016/j.cell.2014.05.016.

The diabetes susceptibility gene clec16a regulates mitophagy.

Soleimanpour, SA; Gupta, A; Bakay, M; Ferrari, AM; Groff, DN; Fadista, J; Spruce, LA; Kushner, JA; Groop, L; Seeholzer, SH; Kaufman, BA; Hakonarson, H; Stoffers, DA

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, Endo

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.

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