Abstract
Rab37 belongs to a subclass of Rab GTPases regulating exocytosis, including also Rab3a and Rab27a. Proteomic studies indicate that Rab37 is associated with insulin-containing large dense core granules of pancreatic β-cells. In agreement with these observations, we detected Rab37 in extracts of β-cell lines and human pancreatic islets and confirmed by confocal microscopy the localization of the GTPase on insulin-containing secretory granules. We found that, as is the case for Rab3a and Rab27a, reduction of Rab37 levels by RNA interference leads to impairment in glucose-induced insulin secretion and to a decrease in the number of granules in close apposition to the plasma membrane. Pull-down experiments revealed that, despite similar functional effects, Rab37 does not interact with known Rab3a or Rab27a effectors and is likely to operate through a different mechanism. Exposure of insulin-secreting cells to proinflammatory cytokines, fatty acids or oxidized low-density lipoproteins, mimicking physiopathological conditions that favor the development of diabetes, resulted in a decrease in Rab37 expression. Our data identify Rab37 as an additional component of the machinery governing exocytosis of β-cells and suggest that impaired expression of this GTPase may contribute to defective insulin release in pre-diabetic and diabetic conditions.
Highlights
Diabetes mellitus is a metabolic disorder developing when the organism becomes unable to maintain optimal blood glucose levels [1]
A fluorescently labelled construct encoding wild-type Rab37 fused to EGFP (Rab37wt-EGFP) transfected in INS-1E or MIN6B1 cells colocalized with fluorescently labelled Neuropeptide Y (NPY-mRFP), which is targeted to large-dense core vesicles (LDCVs) [20] (Fig. 1C)
Fine-tuning of insulin release relies on the formation of SNARE complexes, the activation of Ca2+-binding proteins and on the function of several GTPases including the members of the Rab3 and Rab27 families [27]
Summary
Diabetes mellitus is a metabolic disorder developing when the organism becomes unable to maintain optimal blood glucose levels [1]. Among the components orchestrating hormone release from pancreatic b-cells are the GTPases Rab3a and Rab27a that play a central role in the late events of the secretory pathway [4]. These GTPases have been found to interact with a large set of effectors and to contribute to the control of docking and fusion of insulin-containing granules. Rab has been reported to participate in regulated secretion in mammalian cells This GTPase displays high sequence homologies with Rab3a and Rab27a and has been localized on secretory granules of mastocytes [5] and Natural Killer cell secretory lysosomes [6]
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