Using the Drosophila prothoracic gland as a model to study the dynamic control of cellular iron availability and trafficking, the Drosophila gene AGBE was determined to play a role in cellular iron homeostasis. In insects, the prothoracic gland is an endocrine tissue mainly devoted to the production of steroid hormones. In both vertebrates and insects, the synthesis of steroid hormones is highly dependent on enzymes that require heme and Fe-S clusters. Dmel\AGBE is orthologous to the human gene GBE1, which encodes a glycogen branching enzyme required for normal glycogen accumulation and that impacts the solubility of glycogen. Human GBE1 is implicated in glycogen storage disease 1 (MIM:232500). A role for this enzyme in cellular iron homeostasis is a new finding.
Multiple genetic reagents have been generated for Dmel\AGBE, including RNAi-targeting constructs, alleles caused by insertional mutagenesis, and a CRISPR/Cas9-mediated knockout construct. The human GBE1 gene has not been introduced into flies.
The lack of any of several enzymes involved in later stages of heme biosynthesis results in accumulation of fluorescent intermediates, porphyrin or porphyrin precursors. In Drosophila, when the products of these genes are knocked down (via RNAi) in the prothoracic glands and the dissected glands are exposed to UV light, red autofluorescence is observed. This assay was validated by testing orthologs of genes known to be required for biosynthesis of heme and implicated in forms of porphyria in human: Urod (human UROD, MIM:6135210) and Ppox (human PPOX, MIM:600923).
It was observed that knockdown of the fly gene AGBE in the prothoracic gland also results in the autofluorescence phenotype. Unlike knockdown of Urod or Ppox, however, the phenotype caused by reduced AGBE can be rescued by an iron-supplemented diet. It was shown that AGBE interacts physically with the proteins encoded by Irp-1A (Iron regulatory protein 1A, specifically the holoform) and Cisd2; the closest human orthologs of these two genes are ACO1 and CISD2. It is postulated that Cisd2 and AGBE are required to maintain functionality of holo-Irp-1A, possibly by maintaining its Fe–S clusters. The translocation of cytoplasmic holo-Irp-1A to the nucleus is observed in some tissues; the translocation process appears to be dependent upon AGBE. When tested in this Drosophila system, the human Hsap\ACO1 protein is also observed to translocate to the nucleus in specific tissues.
[updated Dec. 2020 by FlyBase; FBrf0222196]
Porphyria is a group of disorders caused by abnormalities in the chemical steps that lead to heme production, resulting in a build-up of porphyrin or porphyrin precursors. High levels of porphyrins accumulate in various different tissues in different types of porphyria. [MedlinePlus, Porphyria; 2020.12.04]
GBE1 is required for normal glycogen accumulation. The GBE1 gene encodes a glycogen branching enzyme that impacts the solubility of glycogen and, consequently, in regulating the osmotic pressure within cells. [Gene Cards, GBE1; 2020.12.04]
One to one: 1 human gene to 1 Drosophila gene.
High-scoring ortholog of human GBE1 (1 Drosophila to 1 human). Dmel\AGBE shares 61% identity and 77% similarity with the human gene.
