Fer1HCH encodes the heavy-chain homolog (H subunit) of Drosophila secreted ferritin. Twelve Fer1HCH and twelve Fer2LCH subunits assemble in the secretory pathway into a 24-mer iron-storage cage that is loaded with iron in the Golgi and secreted into hemolymph. Fer1HCH carries the ferroxidase center that oxidizes Fe(2+) for deposition as a ferric mineral core, and this activity is essential in vivo. Ferritin is required in midgut enterocytes for dietary iron absorption, exporting iron toward the hemolymph, and in other tissues for sequestering and detoxifying excess iron; ferritin loss causes embryonic and early larval lethality. Fer1HCH transcripts carry an iron-responsive element and their processing is regulated by dietary iron. By limiting free iron, Fer1HCH protects growing wing imaginal discs from reactive oxygen species accumulation, mitochondrial damage and ferroptosis, and intestinal and hemocyte Fer1HCH influences blood cell (crystal cell and plasmatocyte) differentiation in the larval lymph gland.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004322 ferroxidase activity | IEA GO_REF:0000003 | ACCEPT | Summary: Ferroxidase (EC 1.16.3.1) from EC mapping. Reason: Fer1HCH retains the H-chain ferroxidase center residues and a ferroxidase-dead Fer1HCH fails to rescue Fer1HCH mutants, so the activity is real and essential. Supporting Evidence: PMID:17603097 Thus, the ferroxidase activity of Fer1HCH provides an essential function in vivo and is likely required for iron loading of the ferritin shell. PMID:17603097 The H subunit contains a ferroxidase center, which enables the mature heteropolymer to oxidize soluble ferrous iron, whereas the L chain provides the nucleation centers for deposition of the ferrihydrite mineral |
| GO:0005576 extracellular region | EXP PMID:11804801 Drosophila melanogaster ferritin: cDNA encoding a light chai... | ACCEPT | Summary: Secreted ferritin is detected in larval and adult hemolymph. Reason: Insect ferritin is predominantly a secreted heteropolymer that circulates in hemolymph; this is a defining feature distinguishing it from vertebrate cytosolic ferritin. Supporting Evidence: PMID:17603097 In vivo expression of GFP-tagged holoferritin confirmed that iron-loaded ferritin molecules traffic through the Golgi organelle and are secreted into hemolymph. PMID:11804801 Ferritin is abundant in gut and hemolymph of larvae and adults |
| GO:0005576 extracellular region | EXP PMID:26192321 Ferritin Is Required in Multiple Tissues during Drosophila m... | ACCEPT | Summary: Fluorescently tagged Fer1HCH is secreted via the COPII-dependent secretory pathway. Reason: Experimental support for secretion of fly ferritin. Supporting Evidence: PMID:26192321 Overall, our results are consistent with insect ferritin combining three functions: iron storage, intercellular iron transport, and protection from iron-induced oxidative stress. PMID:17603097 In vivo expression of GFP-tagged holoferritin confirmed that iron-loaded ferritin molecules traffic through the Golgi organelle and are secreted into hemolymph. |
| GO:0005576 extracellular region | HDA PMID:15466469 Proteomic analysis of the Drosophila larval hemolymph clot. | ACCEPT | Summary: Ferritin identified in cell-free larval hemolymph proteome. Reason: High-throughput detection consistent with the well-established secretion of fly ferritin. Supporting Evidence: PMID:15466469 our two-dimensional protein map of cell-free Drosophila hemolymph includes many additional proteins PMID:17603097 In vivo expression of GFP-tagged holoferritin confirmed that iron-loaded ferritin molecules traffic through the Golgi organelle and are secreted into hemolymph. |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location "Secreted" mapping. Reason: Supported by experimental evidence for secretion into hemolymph. Supporting Evidence: PMID:17603097 In vivo expression of GFP-tagged holoferritin confirmed that iron-loaded ferritin molecules traffic through the Golgi organelle and are secreted into hemolymph. |
| GO:0005794 Golgi apparatus | IDA PMID:17603097 Homeostatic mechanisms for iron storage revealed by genetic ... | ACCEPT | Summary: GFP-tagged ferritin localizes to the Golgi in midgut iron-region cells. Reason: Direct live-imaging and colocalization with the Golgi marker Lava lamp; iron loading of insect ferritin occurs in the secretory pathway. Supporting Evidence: PMID:17603097 Confocal images from a single cell in the iron region clearly showed that all GFP-ferritin localized within the Golgi compartment PMID:17603097 In vivo expression of GFP-tagged holoferritin confirmed that iron-loaded ferritin molecules traffic through the Golgi organelle and are secreted into hemolymph. |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location "Golgi apparatus" mapping. Reason: Supported by the IDA data from the same study used by UniProt. Supporting Evidence: PMID:17603097 Confocal images from a single cell in the iron region clearly showed that all GFP-ferritin localized within the Golgi compartment |
| GO:0006826 iron ion transport | IEA GO_REF:0000002 | ACCEPT | Summary: Iron ion transport from the ferritin InterPro signature. Reason: Unlike vertebrate ferritin, secreted insect ferritin moves iron between cells (out of enterocytes into hemolymph), so iron transport is a genuine role here. Supporting Evidence: PMID:26192321 Overall, our results are consistent with insect ferritin combining three functions: iron storage, intercellular iron transport, and protection from iron-induced oxidative stress. PMID:23064556 These results suggest an essential role of ferritin in removing iron from enterocytes across the basolateral membrane. |
| GO:0006879 intracellular iron ion homeostasis | IDA PMID:10077577 Iron availability dramatically alters the distribution of fe... | ACCEPT | Summary: Iron-dependent regulation of ferritin subunit messages; ferritin buffers cellular iron. Reason: Ferritin is the main iron-storage protein; the experimental annotation is consistent with the established role in iron homeostasis, and the curator read the full paper. Supporting Evidence: PMID:10077577 Iron significantly increases the amount of ferritin HCH messages PMID:23064556 Drosophila ferritin is essential to two key aspects of iron homeostasis: dietary iron absorption and tissue iron detoxification |
| GO:0006879 intracellular iron ion homeostasis | IEA GO_REF:0000002 | ACCEPT | Summary: Iron homeostasis from the ferritin InterPro signature. Reason: Core role of ferritin. Supporting Evidence: PMID:23064556 Drosophila ferritin is essential to two key aspects of iron homeostasis: dietary iron absorption and tissue iron detoxification |
| GO:0006879 intracellular iron ion homeostasis | NAS PMID:10471706 The Berkeley Drosophila Genome Project gene disruption proje... | ACCEPT | Summary: Author statement of a role in iron homeostasis. Reason: Correct and consistent with experimental data. Supporting Evidence: PMID:23064556 Drosophila ferritin is essential to two key aspects of iron homeostasis: dietary iron absorption and tissue iron detoxification |
| GO:0008198 ferrous iron binding | IDA PMID:10077577 Iron availability dramatically alters the distribution of fe... | ACCEPT | Summary: Ferrous iron binding by the H chain. Reason: The H-chain ferroxidase center binds Fe(2+) before oxidation; defer to the curator, who read the full text, as the activity is biochemically expected. Supporting Evidence: PMID:17603097 The H subunit contains a ferroxidase center, which enables the mature heteropolymer to oxidize soluble ferrous iron, whereas the L chain provides the nucleation centers for deposition of the ferrihydrite mineral |
| GO:0008198 ferrous iron binding | NAS PMID:10471706 The Berkeley Drosophila Genome Project gene disruption proje... | ACCEPT | Summary: Author statement of ferrous iron binding. Reason: Consistent with the H-chain ferroxidase center. Supporting Evidence: PMID:17603097 The H subunit contains a ferroxidase center, which enables the mature heteropolymer to oxidize soluble ferrous iron, whereas the L chain provides the nucleation centers for deposition of the ferrihydrite mineral |
| GO:0008199 ferric iron binding | IEA GO_REF:0000002 | ACCEPT | Summary: Ferric iron binding from the ferritin InterPro signatures. Reason: Ferritin stores iron as a ferric oxyhydroxide core within the 24-mer cage. Supporting Evidence: PMID:17603097 The H subunit contains a ferroxidase center, which enables the mature heteropolymer to oxidize soluble ferrous iron, whereas the L chain provides the nucleation centers for deposition of the ferrihydrite mineral |
| GO:0008283 cell population proliferation | IDA PMID:20628369 Identification of iron-loaded ferritin as an essential mitog... | KEEP AS NON CORE | Summary: Purified iron-loaded ferritin promotes proliferation of cultured imaginal disc cells. Reason: Real experimental effect, but it reflects delivery of iron needed for growth rather than a signaling activity of ferritin itself. Supporting Evidence: PMID:20628369 iron-loaded ferritin acts as an essential mitogen for cell proliferation and postembryonic development |
| GO:0009620 response to fungus | HEP PMID:15556270 Peptidomic and proteomic analyses of the systemic immune res... | KEEP AS NON CORE | Summary: Ferritin abundance in hemolymph changes after microbial (including fungal) challenge. Reason: Expression-pattern evidence; iron withholding by ferritin is a plausible part of nutritional immunity, but the annotation reflects induction rather than a defined immune activity. Supporting Evidence: PMID:15556270 differential analyses of blood content (hemolymph) from immune-challenged versus control Drosophila were performed |
| GO:0009791 post-embryonic development | IMP PMID:20628369 Identification of iron-loaded ferritin as an essential mitog... | KEEP AS NON CORE | Summary: Ferritin mutants arrest at first instar. Reason: Developmental requirement downstream of iron supply; not a core function. Supporting Evidence: PMID:20628369 Ferritin mutant flies arrest development at the first-instar larval stage |
| GO:0030431 sleep | IEP PMID:25409104 Identification of genes associated with resilience/vulnerabi... | MARK AS OVER ANNOTATED | Summary: Transcript level changes in a sleep-deprivation microarray screen. Reason: Expression change during sleep deprivation or starvation is not evidence that ferritin participates in sleep; ferritin is a broadly stress- and iron-responsive gene. Supporting Evidence: PMID:25409104 identify transcripts that are differentially expressed between cyc(01) mutants that had been sleep deprived or starved for 7 h |
| GO:0045169 fusome | IDA PMID:18355804 New components of the Drosophila fusome suggest it plays nov... | KEEP AS NON CORE | Summary: A Fer1HCH protein trap is enriched in the germline fusome. Reason: Localization observed in a protein-trap screen; the same study shows Fer1HCH is dispensable for fusome structure, so this is a minor location. Supporting Evidence: PMID:18355804 By screening a library of protein trap lines, we identified 14 new fusome-enriched proteins PMID:18355804 genetic disruption of tropomodulin, ferritin-1 heavy chain, or scribble, does not alter fusome structure or female fertility |
| GO:0070288 ferritin complex | IDA PMID:10077577 Iron availability dramatically alters the distribution of fe... | ACCEPT | Summary: Fer1HCH and Fer2LCH assemble into the 24-subunit ferritin cage in 1:1 stoichiometry. Reason: The ferritin heteropolymer is the functional unit; subunit membership of the complex is core. Supporting Evidence: PMID:26192321 inside a protein cage formed by 24 ferritin subunits of two types (Fer1HCH and Fer2LCH) in a 1:1 stoichiometry PMID:17603097 The H subunit contains a ferroxidase center, which enables the mature heteropolymer to oxidize soluble ferrous iron, whereas the L chain provides the nucleation centers for deposition of the ferrihydrite mineral |
| GO:0098711 iron ion import across plasma membrane | IMP PMID:23064556 Ferritin is the key to dietary iron absorption and tissue ir... | MODIFY | Summary: Midgut ferritin knockdown traps iron in enterocytes and causes systemic iron deficiency. Reason: The data show ferritin is required for dietary iron absorption by carrying iron out of enterocytes across the basolateral side; this is efflux into hemolymph, not import across the plasma membrane into a cell, and ferritin is not a membrane transporter. Intestinal iron absorption captures the experimental finding. Proposed replacements: intestinal iron absorption Supporting Evidence: PMID:23064556 These results suggest an essential role of ferritin in removing iron from enterocytes across the basolateral membrane. PMID:23064556 Drosophila ferritin is essential to two key aspects of iron homeostasis: dietary iron absorption and tissue iron detoxification |
| GO:1990461 detoxification of iron ion | IMP PMID:23064556 Ferritin is the key to dietary iron absorption and tissue ir... | ACCEPT | Summary: Tissue-specific ferritin knockdown causes local iron accumulation and tissue damage. Reason: Direct genetic evidence that ferritin sequesters and exports excess iron to protect tissues. Supporting Evidence: PMID:23064556 tissue-specific ferritin knockdown also caused local iron accumulation (100% increase) and resulted in severe tissue damage PMID:23064556 Drosophila ferritin is essential to two key aspects of iron homeostasis: dietary iron absorption and tissue iron detoxification |
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Download this section (compressed HTML)Q: What hemolymph receptor or uptake route takes up iron-loaded secreted ferritin in target tissues, and how is iron released from it?
Q: Is the IRE-lacking Fer1HCH mRNA isoform induced by iron loading the main source of Fer1HCH protein under iron overload?
Experiment: Track fluorescently tagged holoferritin injected into or expressed from the gut of ferritin-deficient larvae, and screen candidate endocytic receptors by tissue-specific RNAi for loss of uptake.
Hypothesis: Iron-loaded secreted ferritin is endocytosed by specific tissues such as nephrocytes and the nervous system.
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Download this section (compressed HTML)Ferritin 1 heavy chain homologue (Fer1HCH) encodes one of two subunits of the major iron storage complex, the ferritin molecule. In insects, ferritin is assembled from 12 Fer1HCH and 12 Fer2LCH subunits and can be found in the secretory pathway of cells and in hemolymph. The product of Fer1HCH has ferroxidase activity required for iron loading into ferritin and is essential for embryogenesis.
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