GDF15 maturation requires proteolytic cleavage by PCSK3, 5 and 6.

Growth differentiation factor 15 (GDF15) is a secreted protein with pleotropic functions from the transforming growth factor beta (TGF-beta) 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 such as 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 heart-derived hormone that inhibits liver growth hormone signaling and postnatal body growth in the pediatric period. However, little is known about the mechanism of GDF15 maturation, in particular the enzymes that mediate GDF15 precursor cleavage. 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/kexin-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.