Maturation of Growth Differentiation Factor 15 in Human Placental Trophoblast Cells Depends on the Interaction With Matrix Metalloproteinase-26

CONTEXT: Matrix Metalloproteinase-26 (MMP-26) is the smallest member of matrix metalloproteinase (MMP) family that functions mainly in the extracellular milieu to cleave the extracellular matrix proteins. It is expressed in various cell types of placenta, but its function in placentation has been poorly understood. Considering the existence of a unique cysteine switch sequence in MMP-26 protein sequence, as well as the evidence in cancer cells indicating the digestion of the NH2-terminal domain of ERβ by MMP-26, we hypothesize that MMP-26 may have specific intracellular activity in human placental trophoblast cells. OBJECTIVE: This study aimed to identify the intracellular binding partners of MMP-26 and investigate how MMP-26 is involved in placentation through the interactions with its partners. SETTING AND DESIGN: Yeast two-hybrid system was employed to screen potential binding partners of MMP-26 in human placenta. Immunoprecipitation and immunofluorescence assays were conducted to verify the interactions between MMP-26 and the binding partners. HEK293T and HTR8/SVneo cell lines were used as in vitro models to investigate the roles of the interaction between MMP-26 and its binding partner on cell behaviors. RESULTS: RESULTS of yeast two-hybrid assay, immunoprecipitation, and immunofluorescence assays revealed that MMP-26 could bind to growth differentiation factor 15 (GDF15) in the intracellular milieu. The binding of MMP-26 to GDF15 was responsible for the processing and maturation of pro-GDF15, and the process was dependent on the enzymatic activity of MMP-26. In human placental trophoblast cells, MMP-26 could facilitate the pro-apoptotic effect of GDF15. CONCLUSIONS: This is the first report to demonstrate the physiological function of placental MMP-26 in processing GDF15 and subsequently promoting trophoblast cell apoptosis. These findings expand our understanding of the working mechanism of the metalloproteinase in the process of placentation.