HID1 is a conserved 788-residue peripheral membrane protein of the HID1/Ecm30 family (PANTHER PTHR21575, subfamily SF12) with no recognised catalytic, lipid-binding or protein-interaction domain. Despite early predictions of transmembrane segments, it is a soluble protein that shuttles between the cytosol and the cytoplasmic face of the medial- and trans-Golgi and the trans-Golgi network (TGN). Membrane association depends on an N-terminal myristoylated glycine and an adjacent polybasic patch, while TGN specificity and function reside in a highly conserved C-terminal domain. In neuroendocrine and endocrine cells HID1 is required for the biogenesis of large dense core vesicles (secretory granules): it supports sorting of soluble and membrane cargo into these granules, formation of the dense core, acidification of the TGN with correct localisation of the V-ATPase a2 subunit, and homotypic fusion of immature granules during their maturation, and so the storage and regulated release of peptide hormones and neuropeptides. Most of this functional evidence comes from rat neuroendocrine cell lines and mouse pancreatic beta cells, whose HID1 orthologs are about 95% identical to the human protein; in humans, biallelic HID1 variants cause an early infantile epileptic encephalopathy with hypopituitarism (DEE105). Its molecular activity is unknown.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000138 Golgi trans cisterna | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic propagation from the eukaryote-level node PTN000491103, seeded by human HID1's own IDA and C. elegans hid-1 localization data. Reason: Human HID1 has direct localization evidence for the trans-Golgi cisterna (PMID:21337012), so the target's own experimental annotation is one of the seeds of this IBD, which is expected and not circular. The inherited claim agrees with the direct data and with TGN localization of the rat ortholog (PMID:29074564, PMID:37751424). The trans-Golgi region is where HID1 acts in dense core vesicle biogenesis. Supporting Evidence: PMID:21337012 we revealed that mammalian HID-1 localized to the medial- and trans- Golgi apparatus as well as the cytosol PMID:37751424 HID-1 is a trans-Golgi network (TGN) localized peripheral membrane protein contributing to LDCV formation |
| GO:0000138 Golgi trans cisterna | IDA PMID:21337012 HID-1 is a peripheral membrane protein primarily associated ... | ACCEPT | Summary: Direct localization of mammalian HID1 to the medial- and trans-Golgi by Wang et al. (2011). Reason: The paper's central finding is medial- and trans-Golgi localization of HID1, sensitive to brefeldin A. Only the abstract is cached, so the exact cell lines are not visible here, but the finding is the title claim of the paper and is consistent with all later work on the mammalian protein. Supporting Evidence: PMID:21337012 mammalian HID-1 localized to the medial- and trans- Golgi apparatus as well as the cytosol, and the localization was sensitive to brefeldin A treatment |
| GO:0005515 protein binding | IPI PMID:20368287 Interactome mapping of the phosphatidylinositol 3-kinase-mam... | REMOVE | Summary: Interaction with INPPL1 (SHIP2) from a large PI3K-mTOR pathway interactome screen. Reason: Bare protein binding is uninformative under the repository policy. This is a single interaction from a high-throughput interactome map with no follow-up connecting INPPL1 to HID1 function; removal does not assert that the interaction is false. No more informative molecular function can be derived from it. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Yeast two-hybrid interaction with CSDE1 from the proteome-scale human interactome map. Reason: Bare protein binding from a systematic binary interactome screen carries no functional information, and nothing links CSDE1, an RNA-binding protein, to HID1's Golgi role. Removal follows the GO:0005515 policy and does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Yeast two-hybrid interaction with a CSDE1 isoform from the HuRI reference interactome. Reason: Bare protein binding from a systematic screen is uninformative and has no functional follow-up; removed under the GO:0005515 policy without implying the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Yeast two-hybrid interaction with the peroxisomal enzyme EHHADH from HuRI. Reason: Bare protein binding from a systematic screen, with a peroxisomal partner that has no plausible relation to HID1's cytosol/Golgi function; removed under the GO:0005515 policy. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Yeast two-hybrid interaction with a CELF3 isoform from HuRI. Reason: Bare protein binding from a systematic screen; the RNA-binding partner gives no informative molecular function for HID1. Removed under the GO:0005515 policy. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Yeast two-hybrid interaction with UBL5 from HuRI. Reason: Bare protein binding from a systematic screen without functional follow-up; removed under the GO:0005515 policy. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Interaction with HRAS from a neurodegenerative-disease protein interactome screen. Reason: Bare protein binding from a systematic interaction screen; no study connects HRAS to HID1 function. Removed under the GO:0005515 policy without implying the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Interaction with FGFR3 from a neurodegenerative-disease protein interactome screen. Reason: Bare protein binding from a systematic screen; uninformative and without follow-up. Removed under the GO:0005515 policy. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Interaction with a CHAT isoform from a neurodegenerative-disease protein interactome screen. Reason: Bare protein binding from a systematic screen; uninformative and without follow-up. Removed under the GO:0005515 policy. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Interaction with SPRED1 from a neurodegenerative-disease protein interactome screen. Reason: Bare protein binding from a systematic screen; uninformative and without follow-up. Removed under the GO:0005515 policy. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Interaction with a TSC1 isoform from a neurodegenerative-disease protein interactome screen. Reason: Bare protein binding from a systematic screen; uninformative and without follow-up. Removed under the GO:0005515 policy. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Interaction with UBQLN1 from a neurodegenerative-disease protein interactome screen. Reason: Bare protein binding from a systematic screen; uninformative and without follow-up. Removed under the GO:0005515 policy. |
| GO:0005737 cytoplasm | IDA PMID:21337012 HID-1 is a peripheral membrane protein primarily associated ... | MODIFY | Summary: The non-Golgi pool of HID1 observed by Wang et al. (2011) is cytosolic. Reason: Correct but more general than the evidence. The paper reports a soluble cytosolic pool of HID1 that exchanges with the Golgi-bound pool, which is the specific location GO:0005829 cytosol, a term the gene already carries by IDA and IBA. Proposed replacements: cytosol Supporting Evidence: PMID:21337012 HID-1 was a peripheral membrane protein and dynamically shuttled between the Golgi apparatus and the cytosol |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | MODIFY | Summary: UniProt subcellular-location mapping of the curated 'Cytoplasm' statement. Reason: Same claim as the IDA cytoplasm row, which this mapping derives from; the more precise supported location is cytosol (GO:0005829), already carried by the gene. Proposed replacements: cytosol Supporting Evidence: PMID:21337012 HID-1 was a peripheral membrane protein and dynamically shuttled between the Golgi apparatus and the cytosol |
| GO:0005794 Golgi apparatus | IDA GO_REF:0000052 | MODIFY | Summary: Human Protein Atlas immunofluorescence places HID1 at the Golgi apparatus. Reason: Correct but general. Higher-resolution studies place HID1 specifically on the cytoplasmic face of the medial- and trans-Golgi cisternae and the TGN membrane, all terms the gene already carries; patient-fibroblast immunofluorescence also shows TGN colocalization. Supporting Evidence: PMID:21337012 mammalian HID-1 localized to the medial- and trans- Golgi apparatus PMID:33999436 Colocalization of HID1 protein with the TGN was not altered in fibroblasts of patients compared to controls |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000044 | MODIFY | Summary: UniProt subcellular-location mapping to Golgi apparatus. Reason: The UniProt statement is 'Golgi apparatus, trans-Golgi network membrane'; the mapped term is the general parent. Replace with the specific supported sub-compartments, as for the IDA row. Supporting Evidence: PMID:21337012 mammalian HID-1 localized to the medial- and trans- Golgi apparatus |
| GO:0005797 Golgi medial cisterna | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic propagation from PTN000491103, seeded by human HID1 IDA and C. elegans data. Reason: Consistent with the direct medial-Golgi localization of the human protein, which is itself one of the seeds. Medial-Golgi association is part of the reported distribution, although functional work centres on the TGN. Supporting Evidence: PMID:21337012 mammalian HID-1 localized to the medial- and trans- Golgi apparatus |
| GO:0005797 Golgi medial cisterna | IDA PMID:21337012 HID-1 is a peripheral membrane protein primarily associated ... | ACCEPT | Summary: Direct localization of HID1 to the medial Golgi. Reason: Stated in the title and abstract of the paper; consistent with the IBA row. Supporting Evidence: PMID:21337012 HID-1 is a peripheral membrane protein primarily associated with the medial- and trans- Golgi apparatus |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic propagation of cytosolic location from PTN000491103. Reason: HID1 is a soluble peripheral protein with a cytosolic pool that exchanges with the Golgi pool; the human protein's direct observation is one of the seeds. Supporting Evidence: PMID:21337012 dynamically shuttled between the Golgi apparatus and the cytosol |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas immunofluorescence detects cytosolic HID1. Reason: Agrees with the biochemical and imaging evidence for a cytosolic pool of HID1 that exchanges with the Golgi-bound pool. Supporting Evidence: PMID:21337012 localized to the medial- and trans- Golgi apparatus as well as the cytosol |
| GO:0005881 cytoplasmic microtubule | IDA PMID:23264731 MTR120/KIAA1383, a novel microtubule-associated protein, pro... | MARK AS OVER ANNOTATED | Summary: C17ORF28 (HID1) was listed among putative microtubule-associated proteins in a whole-ORFeome localization screen of tagged overexpressed proteins. Reason: The paper is about MTR120/KIAA1383; HID1 appears only as one of several uncharacterized hits of a high-throughput overexpression localization screen and was not followed up. Dedicated localization studies of the mammalian protein show a cytosolic pool and a Golgi/TGN-bound pool, and no study links HID1 to microtubules. The screen result is not wrong as an observation but is not a supported location of the endogenous protein. Supporting Evidence: PMID:23264731 We identified tubulins, previously characterized MAPs, and putative new MAPs, including several uncharacterized proteins, such as C9ORF9, C16ORF48, ODF3L, TMEM214, C17ORF28 and KIAA1383/MTR120 PMID:23264731 Our study only focuses on one, KIAA1383/MTR120. |
| GO:0007030 Golgi organization | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Placed at the eukaryote-level node PTN000491103 by PAINT, seeded only by the fission yeast HID paralog SPAC17A5.16, whose mutant lacks stacked Golgi. Reason: The PAINT curator judged Golgi organization ancestral to the whole family and placed it at the eukaryote node, with explicit IRD negations on the Schizosaccharomyces-specific paralog branches; human HID1 sits inside the clade that inherits the node. The sole seed, SPAC17A5.16, is in a different subfamily (PTHR21575:SF13, about 32% identity) from human HID1 (SF12), and no SF12 member has been shown to maintain Golgi stack structure. HID1 loss in mammalian cells does perturb TGN function (acidification, V-ATPase a2 localization), so a role in Golgi organization is plausible but is inferred only; the specific SF12 function is dense core vesicle biogenesis. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN000491103 SUPPORTS TRANSFER Eukaryote-level node carrying the Golgi organization IBD, seeded by fission yeast SPAC17A5.16 (SF13). Human HID1 (SF12) descends from it and no loss is documented, but no SF12 member has direct evidence for Golgi stack maintenance. Supporting Evidence: PMID:40899782 Transmission electron microscopy revealed that the SPAC17A5.16 mutant lacks a stacked Golgi apparatus (GA) form, suggesting a role in maintaining GA structure file:human/HID1/HID1-bioinformatics/RESULTS.md is in a different subfamily (SF13) PMID:29074564 HID-1 KO cells also exhibit defects in TGN acidification together with mislocalization of the Golgi-enriched vacuolar H+-ATPase subunit isoform a2 |
| GO:0016020 membrane | IBA GO_REF:0000033 | MODIFY | Summary: Generic membrane location propagated from PTN000491103. Reason: True but uninformative. HID1 is not an integral membrane protein; it associates peripherally with the cytoplasmic face of Golgi and TGN membranes via its myristoylated, polybasic N-terminus. The supported specific locations, already carried by the gene, are the cytoplasmic side of the Golgi membrane and the TGN membrane. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000491103 SUPPORTS TRANSFER Node assertion is correct but generic; its seeds (human, rat and worm HID1) all support the more specific peripheral Golgi/TGN membrane association. Proposed replacements: cytoplasmic side of Golgi membrane trans-Golgi network membrane Supporting Evidence: PMID:37751424 the N-terminus of HID-1 mediates membrane binding through a myristoyl group with a polybasic amino acid patch but lacks specificity for the TGN |
| GO:0032588 trans-Golgi network membrane | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer from rat Hid1 (D4A0C3), an SF12 ortholog about 95% identical to human HID1. Reason: Rat HID1 is a TGN-localized peripheral membrane protein in PC12 and INS-1 cells, and the human protein colocalizes with the TGN in patient and control fibroblasts. The orthology is grounded in shared PANTHER subfamily SF12 and near-identical sequence. Supporting Evidence: PMID:37751424 HID-1 is a trans-Golgi network (TGN) localized peripheral membrane protein contributing to LDCV formation PMID:33999436 Colocalization of HID1 protein with the TGN was not altered in fibroblasts of patients compared to controls file:human/HID1/HID1-bioinformatics/RESULTS.md Human, mouse and rat HID1 share PANTHER subfamily SF12 |
| GO:0032588 trans-Golgi network membrane | ISS GO_REF:0000024 | ACCEPT | Summary: UniProt curator transfer of TGN membrane location from rat Hid1. Reason: Same claim as the IEA row, from the same ortholog; consistent with human fibroblast TGN colocalization. Supporting Evidence: PMID:37751424 HID-1 is a trans-Golgi network (TGN) localized peripheral membrane protein |
| GO:0061110 dense core granule biogenesis | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer from rat Hid1 of its role in large dense core vesicle biogenesis. Reason: Rat HID1 knockout PC12 cells have fewer LDCVs with abnormal morphology, impaired cargo sorting and dense core formation, and rescue requires the TGN-tethered conserved C-terminal domain. HID1 acts at the TGN where granules form, so it does part of the work of biogenesis, although its molecular activity is unknown. Orthology is grounded in shared subfamily SF12. Supporting Evidence: PMID:29074564 Loss of HID-1 causes a reduction in the number of LDCVs and affects their morphology and biochemical properties, due to impaired cargo sorting and dense core formation |
| GO:0061110 dense core granule biogenesis | IMP PMID:37751424 Identification of the functional domain of the dense core ve... | ACCEPT | Summary: Structure-function analysis of HID1, including the DEE105 patient C-terminal frameshift, showing that the conserved C-terminus is required for LDCV cargo sorting and regulated secretion. Reason: The cells (rat PC12 and INS-1 HID1 knockouts) and the rescue constructs (rat HID1 cDNA) are rat, so the IMP for human HID1 rests on modelling the human patient frameshift, which replaces the last 15 residues, in the rat ortholog. The C-terminal region is highly conserved and the orthologs are about 95% identical, so the inference is sound; but the experiment was not done with the human protein. Supporting Evidence: PMID:37751424 this isolated domain, when tethered to the TGN, can rescue the neuroendocrine secretion and sorting defects observed in HID-1 KO cells PMID:37751424 Stable expression of this mutant in HID-1 KO PC12 cells led to proper TGN localization (Fig 5A). However, this mutant completely failed to rescue the secretion phenotype observed in HID-1 KO cells |
| GO:0061110 dense core granule biogenesis | ISS GO_REF:0000024 | ACCEPT | Summary: UniProt curator transfer from rat Hid1. Reason: Same claim as the IEA and IMP rows, grounded in the rat ortholog's knockout phenotype. Supporting Evidence: PMID:29074564 These results establish that the peripheral membrane protein HID-1 is required for LDCV biogenesis from rat neuroendocrine PC12 cells. |
| GO:0061792 secretory granule maturation | IBA GO_REF:0000033 | ACCEPT | Summary: Propagated from node PTN001090684, seeded by mouse Hid1 beta-cell knockout data. Reason: Conditional deletion of Hid1 in mouse beta cells causes accumulation of immature secretory granules, a block in their homotypic fusion and defective proinsulin processing. Mouse Hid1 is in the same subfamily (SF12) and is about 96% identical, and PAINT placed the term at a node below the eukaryote node rather than at PTN000491103, consistent with this being a metazoan specialization. Supporting Evidence: PMID:27751232 HID-1 deficiency prevented secretory granule maturation by blocking homotypic fusion of immature secretory granules |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: HID1 detected in a proteomic inventory of prostatic-secretion exosomes in urine. Reason: A high-throughput proteomic detection; cytosolic proteins are commonly captured in exosome preparations. It does not bear on HID1 function, which is intracellular at the Golgi/TGN. |
| GO:0098548 cytoplasmic side of Golgi membrane | IDA PMID:21337012 HID-1 is a peripheral membrane protein primarily associated ... | ACCEPT | Summary: HID1 is a peripheral protein bound to the cytosolic face of Golgi membranes. Reason: Wang et al. showed HID1 is peripheral, not transmembrane, and that Golgi binding requires the N-terminal myristoylation site; later work confirmed membrane binding through the myristoyl group and polybasic patch. This is the precise membrane topology of HID1. Supporting Evidence: PMID:21337012 we verified that a conserved N-terminal myristoylation site was required for HID-1 binding to the Golgi apparatus PMID:37751424 HID-1 behaves as a peripheral membrane protein that associates with the TGN from the cytosol |
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Download this section (compressed HTML)Q: Does HID1 act directly on the Golgi V-ATPase (for example on a2-subunit trafficking or assembly), or is mislocalization of a2 a secondary consequence of defective granule formation?
Q: Is the Golgi organization IBA, seeded only by the SF13 fission yeast paralog SPAC17A5.16, appropriate for metazoan SF12 members whose experimentally shown role is dense core vesicle biogenesis?
Q: Do any of the DEE105 missense variants (for example p.R433W) disrupt dense core vesicle biogenesis when expressed as the human protein in HID1-null neuroendocrine cells?
Experiment: Identify direct binding partners of the conserved C-terminal domain (residues ~686-788) by proximity labelling at the TGN in HID1-knockout neuroendocrine cells rescued with TGN-tethered human HID1, and test candidates by in vitro binding with purified protein.
Type: proximity labelling and in vitro reconstitution
Experiment: Rescue HID1-knockout PC12 or INS-1 cells with human HID1 wild type and DEE105 patient variants, measuring secretogranin sorting, regulated secretion and TGN pH, to establish the activity directly for the human protein.
Type: complementation assay
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