Characterization of a Novel Pathway for Transmembrane Proteins Found on Insulin Granules

Regulated exocytosis of insulin in response to hyperglycemia is essential for glucose homeostasis, but the mechanisms determining insulin granule formation remains unclear. Synaptotagmins are a family of transmembrane proteins, with some members found on the insulin granule acting as calcium sensors, contributing to regulated exocytosis. The textbook model suggests that all proteins found on insulin granules are sorted during their formation at the trans-Golgi network. We now report that synaptotagmin-5 (Syt-5), one of the transmembrane proteins found on mature insulin granules, does not sort onto the insulin granule at the trans-Golgi network. Instead, Syt-5 appears to traffic through the Golgi and take a constitutive pathway to the plasma membrane. After re-internalization, Syt-5 travels to endosomes before being sorted onto insulin granules. It will be interesting to further unravel the biological significance of this more sophisticated model of insulin granule formation.