Cleavage of FNDC5 and insights into its maturation process

FNDC5 corresponds to an irisin precursor that increases with exercise. Studies suggest that irisin mediates beneficial effects in adipose tissues, skeletal muscle, bone, and brain. However, the cleavage and maturation processes of FNDC5 have not been clearly identified. This study aimed to show that the signal peptide and transmembrane domain of FNDC5 were associated with the secretion of its ectodomain. Localization studies identified the signal peptide that was responsible for endoplasmic reticulum targeting activity of nascent FNDC5 and showed that the FNDC5 ectodomain corresponding to irisin could be transported across the membrane by a transmembrane domain. Analysis of cleavage constructs revealed that the ectodomain of FNDC5 could be cleaved from its signal peptide and transmembrane attachment. Genetic ablation of the signal peptide cleavage site blocked N-glycosylation of FNDC5. Identification of the FNDC5 maturation process should facilitate our understanding of irisin secretion.