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, 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.

Functions of Vertebrate Ferlins

“…Myoblasts isolated from dysferlinopathy patients or derived from dysferlin-deficient mice proliferated with the normal rate [117,118], but showed decreased fusion efficiency in vitro as a result of activated signaling of the pro-inflammatory network inhibiting myogenesis [118]. In this context it is important to mention that dysferlin has been found in a protein complex with minion/myomerger, a fusogenic protein, which together with myomaker conveys the ability to form syncytia to myogenic and non-myogenic cells [119].…”

The fusogenic synapse at a glance

“…While syncytins are captured virus fusogens in trophoblasts (Blond et al, 2000;Huppertz and Borges, 2008;Mi et al, 2000), Eff-1 and its paralog Aff-1 in C. elegans epithelial and vulval cells, respectively (Mohler et al, 2002;Sapir et al, 2007), and HAP2 (also known as GCS1) in protist and plant gametes (Liu et al, 2008;Pinello et al, 2017;Valansi et al, 2017) resemble type II viral fusogens (Pérez-Vargas et al, 2014;Fédry et al, 2017). Interestingly, vertebrate myoblast fusion utilizes a bipartite fusogen comprising a seven-pass transmembrane protein myomaker (Millay et al, 2013), and a micropeptide myomixer (also known as myomerger or minion) (Bi et al, 2017;Quinn et al, 2017;Zhang et al, 2017). These two proteins work independently to control distinct steps of membrane remodeling during myoblast fusion, with myomaker involved in membrane hemifusion and myomixer in generating the membrane stress necessary for fusion pore formation (Leikina et al, 2018).…”

An Improved Human smORF Annnotation Workflow Combining De Novo Transcriptome Assembly and Ribo-Seq

“…Functional inferences can also be drawn from microprotein sequence conservation (Fig. 4d-f), as several characterized smORFs have excellent conservation by PhyloCSF and BLAST 13–17 . Having identified thousands of smORFs, additional biological data can easily be mined to elucidate their roles.…”

“…Recently, several mammalian microproteins have been characterized with fundamental roles in cell biology ranging from DNA repair 13 , mitochondrial function 14,15 , and RNA regulation 16 . In addition, microproteins that regulate physiological processes including muscle development 17 , muscle function 18,19 , and metabolism 20 have been discovered. Together these studies demonstrated that genomes contain many functional smORFs and renewed interest in annotating all protein-coding smORFs.…”