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.
Highlights
Multicellular organisms contain specialised cells in appropriate parts of the body, performing tasks that allow the formation and maintenance of a fully functional organism
A small Open Reading Frames (smORFs) gene that encodes a transmembrane peptide of 88 amino-acids expressed in Drosophila macrophages, and we show that Hemotin localizes to early endosomes–vesicles involved in the traffic of material between the cell membrane and the cytoplasm
Macrophages found in hemotin mutants have enlarged and abnormal endosomes that delay digestion of phagocytosed bacteria
Summary
Multicellular organisms contain specialised cells in appropriate parts of the body, performing tasks that allow the formation and maintenance of a fully functional organism. This specialisation relies upon the modification of basic cellular processes, for example enhanced cytoskeletal mechanics in muscle cells, or enhanced endocytic activity in phagocytic cells [1]. At the molecular level, such modifications rely on tissue-specific gene products that regulate specific cell biology and physiology pathways. These regulators offer great promise as specific therapeutic targets, yet for many tissues we still ignore their identity and mechanism of action. The few examples of these smORFs with annotated function are widely expressed and involved in housekeeping processes, such as oxidative phosphorylation in mitochondria [3], but in principle these hydrophobic smORFs have the capacity to act as regulators in other membrane-based cellular processes, as the sarcolamban/sarcolipin smORF family of calcium signalling regulators illustrates [7,11]
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