1. GDF15 maturation requires proteolytic cleavage by PCSK3, 5 and 6.
- Author
-
Jing Jing Li, Jian Liu, Katherine Lupino, Xueyuan Liu, Lili Zhang, and Liming Pei
- Subjects
MYOSTATIN ,TRANSFORMING growth factors-beta ,SUBTILISINS ,CACHEXIA treatment ,OBESITY treatment - Abstract
Growth differentiation factor 15 (GDF15) is a secreted protein with pleotropic functions from the transforming growth factor-β (TGFβ) family. GDF15 is synthesized as a precursor and undergoes proteolytic cleavage to generate mature GDF15. The strong appetite-suppressing effect of mature GDF15 makes it an attractive therapeutic agent/target for diseases including obesity and cachexia. In addition, clinical studies indicate that circulating, mature GDF15 is an independent biomarker for heart failure. We recently found that GDF15 functions as a heart8 derived hormone that inhibits liver growth hormone signaling and postnatal body growth in the pediatric period. However, the mechanism of GDF15 maturation, in particular the enzymes that mediate GDF15 precursor cleavage, is little known. We investigated which candidate proteases can cleave GDF15 precursor and generate mature GDF15 in cardiomyocytes in vitro and mouse hearts in vivo. We discovered that three members of the proprotein convertase, subtilisin/kexin13 type (PCSK) family, namely PCSK3, PCSK5 and PCSK6, can efficiently cleave GDF15 precursor therefore licensing its maturation both in vitro and in vivo. Our studies suggest that PCSK3, 5 and 6 mediate a crucial step of GDF15 maturation through proteolytic cleavage of the precursor. These results also reveal new targets for therapeutic application of GDF15 in treating obesity and cachexia. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF