HID-1, a New Component of the Peptidergic Signaling Pathway

Abstract

hid-1 was originally identified as a Caenorhabditis elegans gene encoding a novel conserved protein that regulates the decision to enter into the enduring dauer larval stage. We isolated a novel allele of hid-1 in a forward genetic screen for mutants mislocalizing RBF-1 rabphilin, a RAB-27 effector. Here we demonstrate that HID-1 functions in the nervous system to regulate neuromuscular signaling and in the intestine to regulate the defecation motor program. We further show that a conserved N-terminal myristoylated motif of both invertebrate and vertebrate HID-1 is essential for its association with intracellular membranes in nematodes and PC12 cells. C. elegans neuronal HID-1 resides on intracellular membranes in neuronal cell somas; however, the kinesin UNC-104 also transports HID-1 to synaptic regions. HID-1 accumulates in the axons of unc-13 and unc-31 mutants, suggesting it is associated with neurosecretory vesicles. Consistent with this, genetic studies place HID-1 in a peptidergic signaling pathway. Finally, a hid-1 null mutation reduces the levels of endogenous neuropeptides and alters the secretion of fluorescent-tagged cargos derived from neuronal and intestinal dense core vesicles (DCVs). Taken together, our findings indicate that HID-1 is a novel component of a DCV-based neurosecretory pathway and that it regulates one or more aspects of the biogenesis, maturation, or trafficking of DCVs.

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

“…Subsequently, hid-1 has been isolated by a genetic screen for mutants mislocalizing rabphilin (RBF-1 in C. elegans ), an effector of RAB-27 that is involved in SG exocytosis (Mesa et al, 2011). The Hid1 gene encodes a highly conserved protein (HID-1) that has homologs in Drosophila melanogaster , mouse, and Homo sapiens , but not in budding yeast.…”

The EARP Complex and its Interactor EIPR-1 are Required for Cargo Sorting to Dense-Core Vesicles

“…Despite the 59 importance of the signaling molecules released by dense-core vesicles, surprisingly little is known 60 about how dense-core vesicles are generated and acquire their proper cargos (1-4). 61 Dense-core vesicles originate at the trans-Golgi network, but it is unclear how their 62 compartmental identity is established and how cargos are correctly sorted into nascent dense-63 core vesicles. After budding from the trans-Golgi, immature dense-core vesicles undergo a poorly 64 defined maturation process that involves homotypic vesicle fusion, peptide processing, and the 5 Molecular mechanisms of dense-core vesicle biogenesis are poorly understood largely 76 because few proteins have been identified that function in this process.…”

Pharyngeal pumping inhibition and avoidance by acute exposure to high CO2levels are both regulated by the BAG neurons via different molecular pathways

“…23,25 By tissue specifically expressing HID-1 in a hid-1 null background, either in the gut (under a ges-1 promoter) or in the nervous system (under a rab-3 promoter), we demonstrated that hid-1 is only needed in the nervous system to mediate pumping inhibition. 19 We next searched for the neuronal subtype in which hid-1 mediates the effect of CO 2 on the pharynx.…”

“…22 HID-1 was also found to be an important component of dense core vesicle secretion that controls neuropeptide release. [23][24][25] Interestingly, the response of this mutant to high CO 2 is dose dependent. After exposure to 5% CO 2 , the pumping inhibition is completely rescued and pumping continues at the same rate as under normal atmospheric conditions.…”