The microprotein Minion controls cell fusion and muscle formation

Abstract

Although recent evidence has pointed to the existence of small open reading frame (smORF)-encoded microproteins in mammals, the functional repertoire of this microproteome remains to be determined1. In skeletal muscle, proper development requires fusion of mononuclear progenitors to form multinucleated myotubes, a critical but poorly understood process2,3. Here we report the identification of a small ORF encoding an essential skeletal muscle specific microprotein we term Minion (microprotein inducer of fusion). Myogenic progenitors lacking Minion differentiate normally but fail to form syncytial myotubes, and Minion-deficient mice die perinatally with marked reduction in fused muscle fibers. This fusogenic activity is conserved to the human Minion ortholog, previously annotated as a long noncoding RNA. Loss-of-function studies demonstrate that Minion is the factor providing muscle specific fusogenic function for the transmembrane protein Myomaker4. Remarkably, we demonstrate that co-expression of Minion and Myomaker is sufficient to induce rapid cytoskeletal rearrangement and homogeneous cellular fusion, even in non-muscle cells. These findings establish Minion as a novel microprotein required for muscle development, and define a two-component program for the induction of mammalian cell fusion, enabling both research and translational applications. Importantly, these data also significantly expand the known functions of smORF-encoded microproteins, an under-explored source of proteomic diversity.