title: Secreted cysteine proteases of the carcinogenic liver fluke, Opisthorchis viverrini: regulation of cathepsin F activation by autocatalysis and trans-processing by cathepsin B.
abstract: Opisthorchis viverrini is an important helminth pathogen of humans that is endemic in Thailand and Laos. Adult flukes reside within host bile ducts and feed on epithelial tissue and blood cells. Chronic opisthorchiasis is associated with severe hepatobiliary diseases such as cholangiocarcinoma. Here we report that adult O. viverrini secrete two major cysteine proteases: cathepsin F (Ov-CF-1) and cathepsin B1 (Ov-CB-1). Ov-CF-1 is secreted as an inactive zymogen that autocatalytically processes and activates to a mature enzyme at pH 4.5 via an intermolecular cleavage at the prosegment-mature domain junction. Ov-CB-1 is also secreted as a zymogen but, in contrast to Ov-CF-1, is fully active against peptide and macromolecular substrates despite retaining the N-terminal prosegment. The active Ov-CB-1 zymogen was capable of trans-activating Ov-CF-1 by proteolytic removal of its prosegment at pH 5.5, a pH at which the Ov-CF-1 zymogen cannot autocatalytically activate. Both cathepsins hydrolyse human haemoglobin but their combined action more efficiently degrades haemoglobin to smaller peptides than each enzyme alone. Ov-CF-1 degraded extracellular matrix proteins more effectively than Ov-CB-1 at physiological pH. We propose that Ov-CB-1 regulates Ov-CF-1 activity and that both enzymes work together to degrade host tissue contributing to the development of liver fluke-associated cholangiocarcinoma.
authors.affiliation: Department of Parasitology, Khon Kaen University, Thailand.
authors.forename: Jittiyawadee
authors.initials: J
authors.lastname: Sripa
authors.forename: Thewarach
authors.initials: T
authors.lastname: Laha
authors.forename: Joyce
authors.initials: J
authors.lastname: To
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Brindley
authors.forename: Banchob
authors.initials: B
authors.lastname: Sripa
authors.forename: Sasithorn
authors.initials: S
authors.lastname: Kaewkes
authors.forename: John P
authors.initials: JP
authors.lastname: Dalton
authors.forename: Mark W
authors.initials: MW
authors.lastname: Robinson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002401:Cathepsin B / Q000378:metabolism*; D056646:Cathepsin F / Q000378:metabolism*; D018509:DNA, Helminth / Q000737:chemistry / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D015801:Helminth Proteins / Q000378:metabolism*; D006454:Hemoglobins / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009891:Opisthorchis / Q000201:enzymology* / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D017422:Sequence Analysis, DNA
chemical_list: D018509:DNA, Helminth; D016326:Extracellular Matrix Proteins; D015801:Helminth Proteins; D006454:Hemoglobins; D002401:Cathepsin B; D056646:Cathepsin F