Abstract
Although recent evidence has pointed to the existence of small open reading frame (smORF)-encoded microproteins in mammals, their function remains to be determined. Skeletal muscle development requires fusion of mononuclear progenitors to form multinucleated myotubes, a critical but poorly understood process. Here we report the identification of Minion (microprotein inducer of fusion), a smORF encoding an essential skeletal muscle specific microprotein. Myogenic progenitors lacking Minion differentiate normally but fail to form syncytial myotubes, and Minion-deficient mice die perinatally and demonstrate a marked reduction in fused muscle fibres. The fusogenic activity of Minion is conserved in the human orthologue, and co-expression of Minion and the transmembrane protein Myomaker is sufficient to induce cellular fusion accompanied by rapid cytoskeletal rearrangement, even in non-muscle cells. These findings establish Minion as a novel microprotein required for muscle development, and define a two-component programme for the induction of mammalian cell fusion. Moreover, these data also significantly expand the known functions of smORF-encoded microproteins.
Highlights
Recent evidence has pointed to the existence of small open reading frame-encoded microproteins in mammals, their function remains to be determined
In this study we report the discovery of a novel small open reading frame (smORF)-encoded essential microprotein which we term Minion
We demonstrate that Minion is required for skeletal muscle development, and together with Myomaker defines a minimal two-component programme for the induction of mammalian cell fusion
Summary
Recent evidence has pointed to the existence of small open reading frame (smORF)-encoded microproteins in mammals, their function remains to be determined. The fusogenic activity of Minion is conserved in the human orthologue, and co-expression of Minion and the transmembrane protein Myomaker is sufficient to induce cellular fusion accompanied by rapid cytoskeletal rearrangement, even in non-muscle cells These findings establish Minion as a novel microprotein required for muscle development, and define a two-component programme for the induction of mammalian cell fusion. These data significantly expand the known functions of smORF-encoded microproteins. In addition to canonically defined protein-coding genes, recent studies have indicated the existence of a new class of mammalian genes[1] These small open reading frames (smORFs) are transcribed and translated by usual means, but are largely unrecognized as protein-coding genes by virtue of their size, typically encoding microproteins o100 amino acids (aa) in length[2]. In addition to the implications for muscle biology, these data significantly expand the known functions of smORF-encoded microproteins, an under-explored source of proteomic diversity
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