Proteolytic processing of secretory pathway kinase Fam20C by site-1 protease promotes biomineralization

Significance Fam20C is the bona fide “Golgi casein kinase” and generates the majority of the secreted phosphoproteome. Loss-of-functionFAM20C mutations cause a type of lethal osteosclerotic bone dysplasia called Raine syndrome. In this study, we find that Fam20C resides in the Golgi apparatus as a transmembrane protein. Site-1 protease, a key regulator of cholesterol homeostasis, cleaves the Fam20C propeptide and promotes its secretion and activation. This proteolytic processing of Fam20C is critical for osteoblast differentiation and mineralization. Our results have important implications for both secretory pathway kinase regulation and biomineralization regulation.