HID-1 is required for homotypic fusion of immature secretory granules during maturation

Abstract

Secretory granules, also known as dense core vesicles, are generated at the trans-Golgi network and undergo several maturation steps, including homotypic fusion of immature secretory granules (ISGs) and processing of prehormones to yield active peptides. The molecular mechanisms governing secretory granule maturation are largely unknown. Here, we investigate a highly conserved protein named HID-1 in a mouse model. A conditional knockout of HID-1 in pancreatic β cells leads to glucose intolerance and a remarkable increase in the serum proinsulin/insulin ratio caused by defective proinsulin processing. Large volume three-dimensional electron microscopy and immunofluorescence imaging reveal that ISGs are much more abundant in the absence of HID-1. We further demonstrate that HID-1 deficiency prevented secretory granule maturation by blocking homotypic fusion of immature secretory granules. Our data identify a novel player during the early maturation of immature secretory granules.DOI: http://dx.doi.org/10.7554/eLife.18134.001

The dense‐core vesicle maturation protein CCCP‐1 binds RAB‐2 and membranes through its C‐terminal domain

“…There are several steps in DCV maturation that involve membrane fusion reactions that may require tethering molecules. One is the homotypic fusion of immature DCVs, a process recently shown to involve the HID‐1 protein . Interestingly, hid‐1 mutants in C .…”

“…One is the homotypic fusion of immature DCVs, 4,18,46 a process recently shown to involve the HID-1 protein. 47 Interestingly, hid-1 mutants in C. elegans have defects in locomotion and DCV cargo sorting similar to cccp-1 and rab-2 mutants, 21,48,49 suggesting that RAB-2 and CCCP-1 may also be important for homotypic fusion of immature DCVs. Also, a recent human exome-sequencing project identified probably causative mutations in the human orthologs of hid-1 and cccp-1 in two people with a range of similar neurological symptoms.…”

EIPR1 controls dense-core vesicle cargo retention and EARP complex localization in insulin-secreting cells

“…Ortolá, Topalidou et al, 2019), suggesting that they both act at a post-Golgi step during DCV maturation. This is in contrast to other known regulators of DCV biogenesis such as PICK1, ICA69, and HID-1 that are needed to control the budding of immature DCVs from the TGN and whose loss leads to a defect in the processing of proinsulin to insulin (Cao, Mao, et al, 2013;Holst, Madsen, et al, 2013;Du, Zhou, Zhao, Cheng, et al, 2016;Hummer et al, 2017). Our findings suggest that EIPR1 and CCDC186 act at a later step in DCV biogenesis than PICK1, ICA69, and HID-1.…”

HID-1 controls cargo sorting and dense core formation by influencingtrans-Golgi network acidification in neuroendocrine cells

“…More recently, it has been reported that conditional KO mice, in which HID-1 has been specifically inactivated from beta-cells of the pancreas, display impaired insulin secretion. This phenotype has been attributed to a defect in homotypic fusion of immature insulin granules (Du et al, 2016), a mechanism that is somewhat surprising considering that this fusion process had never been previously observed in this cell type. Although we cannot definitively rule out that this might contribute to our phenotype, we did not observe any obvious defects in LDCV homotypic fusion in our HID-1 KO PC12 cells by electron microscopy.…”

“…A forward genetic screen in the model organism C. Elegans has previously identified HID-1 as a factor implicated in neuropeptide sorting and secretion (Mesa et al, 2011). HID-1 null worms display reduced levels of LDCV soluble cargo and impaired neurosecretion (Mesa et al, 2011, and conditional knockout (KO) mice lacking HID-1 in beta-cells of the pancreas display a defect in insulin secretion (Du et al, 2016), suggesting that this factor might be significant for glucose homeostasis. Interestingly, HID-1 is a peripheral membrane protein associated with the Golgi/TGN and its expression seems restricted to specialized secretory cells , suggesting that it might directly contribute to LDCV biogenesis.…”