title: Hemotin, a Regulator of Phagocytosis Encoded by a Small ORF and Conserved across Metazoans.
abstract: Translation of hundreds of small ORFs (smORFs) of less than 100 amino acids has recently been revealed in vertebrates and Drosophila. Some of these peptides have essential and conserved cellular functions. In Drosophila, we have predicted a particular smORF class encoding ~80 aa hydrophobic peptides, which may function in membranes and cell organelles. Here, we characterise hemotin, a gene encoding an 88aa transmembrane smORF peptide localised to early endosomes in Drosophila macrophages. hemotin regulates endosomal maturation during phagocytosis by repressing the cooperation of 14-3-3ζ with specific phosphatidylinositol (PI) enzymes. hemotin mutants accumulate undigested phagocytic material inside enlarged endo-lysosomes and as a result, hemotin mutants have reduced ability to fight bacteria, and hence, have severely reduced life span and resistance to infections. We identify Stannin, a peptide involved in organometallic toxicity, as the Hemotin functional homologue in vertebrates, showing that this novel regulator of phagocytic processing is widely conserved, emphasizing the significance of smORF peptides in cell biology and disease.
authors.affiliation: Brighton and Sussex Medical School, University of Sussex, Brighton, United Kingdom.
authors.forename: José I
authors.initials: JI
authors.lastname: Pueyo
authors.affiliation: Brighton and Sussex Medical School, University of Sussex, Brighton, United Kingdom.
authors.forename: Emile G
authors.initials: EG
authors.lastname: Magny
authors.affiliation: School of Life Sciences, University of Sussex, Brighton, United Kingdom.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Sampson
authors.affiliation: School of Life Sciences, University of Sussex, Brighton, United Kingdom.
authors.forename: Unum
authors.initials: U
authors.lastname: Amin
authors.affiliation: Department of Infection and Immunity and the Bateson Centre, University of Sheffield, Sheffield, South Yorkshire, United Kingdom.
authors.forename: Iwan R
authors.initials: IR
authors.lastname: Evans
authors.affiliation: Brighton and Sussex Medical School, University of Sussex, Brighton, United Kingdom.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Bishop
authors.affiliation: Brighton and Sussex Medical School, University of Sussex, Brighton, United Kingdom.
authors.forename: Juan P
authors.initials: JP
authors.lastname: Couso
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D017124:Conserved Sequence; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster; D011992:Endosomes / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D008969:Molecular Sequence Data; D009479:Neuropeptides / Q000235:genetics*; D016366:Open Reading Frames; D010587:Phagocytosis; D017386:Sequence Homology, Amino Acid
chemical_list: D048948:14-3-3 Proteins; D029721:Drosophila Proteins; D009479:Neuropeptides; C000609625:hemo protein, zebrafish; C075692:stannin