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

Author:

Chen XinxinORCID,Zhang Jianchao,Liu Pulan,Wei YangyangORCID,Wang Xi’e,Xiao JunyuORCID,Wang Chih-chen,Wang LeiORCID

Abstract

Family with sequence similarity 20C (Fam20C), the major protein kinase in the secretory pathway, generates the vast majority of the secreted phosphoproteome. However, the regulatory mechanisms of Fam20C transport, secretion, and function remain largely unexplored. Here, we show that Fam20C exists as a type II transmembrane protein within the secretory compartments, with its N-terminal signal peptide-like region serving as a membrane anchor for Golgi retention. The secretion and kinase activity of Fam20C are governed by site-1 protease (S1P), a key regulator of cholesterol homeostasis. We find that only mature Fam20C processed by S1P functions in osteoblast differentiation and mineralization. Together, our findings reveal a unique mechanism for Fam20C secretion and activation via proteolytic regulation, providing a molecular link between biomineralization and lipid metabolism.

Funder

Chinese Academy of Sciences

National Natural Science Foundation of China

Ministry of Science and Technology of the People's Republic of China

Youth Innovation Promotion Association of the Chinese Academy of Sciences

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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