title: Maturation of growth differentiation factor 15 in human placental trophoblast cells depends on the interaction with Matrix Metalloproteinase-26.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
authors.affiliation: State Key Laboratory of Reproductive Biology (S.L., B.C., Y.Wu., L.J., Y.-x.L., M.L., Ha.W., Ho.W., C.H., Y.-l.W.), Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Department of Obstetrics and Gynecology (Y.Wa., Y.Z., J.Q.), Peking University Third Hospital, Beijing 100191, China; and University of Chinese Academy of Sciences (S.L.), Beijing 100049, China.
authors.forename: Sisi
authors.initials: S
authors.lastname: Li
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Wang
authors.forename: Bin
authors.initials: B
authors.lastname: Cao
authors.forename: Yujian
authors.initials: Y
authors.lastname: Wu
authors.forename: Lei
authors.initials: L
authors.lastname: Ji
authors.forename: Yu-xia
authors.initials: YX
authors.lastname: Li
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.forename: Yangyu
authors.initials: Y
authors.lastname: Zhao
authors.forename: Jie
authors.initials: J
authors.lastname: Qiao
authors.forename: Haibing
authors.initials: H
authors.lastname: Wang
authors.forename: Hongmei
authors.initials: H
authors.lastname: Wang
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Han
authors.forename: Yan-ling
authors.initials: YL
authors.lastname: Wang
mesh_terms: D017209:Apoptosis / Q000502:physiology; D005260:Female; D055436:Growth Differentiation Factor 15 / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D053505:Matrix Metalloproteinases, Secreted / Q000378:metabolism*; D010920:Placenta / Q000378:metabolism*; D010929:Placentation / Q000502:physiology; D011247:Pregnancy; D014327:Trophoblasts / Q000378:metabolism*
chemical_list: C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; C410599:MMP26 protein, human; D053505:Matrix Metalloproteinases, Secreted