title: The serine protease hepsin mediates urinary secretion and polymerisation of Zona Pellucida domain protein uromodulin.
abstract: Uromodulin is the most abundant protein in the urine. It is exclusively produced by renal epithelial cells and it plays key roles in kidney function and disease. Uromodulin mainly exerts its function as an extracellular matrix whose assembly depends on a conserved, specific proteolytic cleavage leading to conformational activation of a Zona Pellucida (ZP) polymerisation domain. Through a comprehensive approach, including extensive characterisation of uromodulin processing in cellular models and in specific knock-out mice, we demonstrate that the membrane-bound serine protease hepsin is the enzyme responsible for the physiological cleavage of uromodulin. Our findings define a key aspect of uromodulin biology and identify the first in vivo substrate of hepsin. The identification of hepsin as the first protease involved in the release of a ZP domain protein is likely relevant for other members of this protein family, including several extracellular proteins, as egg coat proteins and inner ear tectorins.
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Brunati
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Perucca
authors.affiliation: Department of Biosciences and Nutrition & Center for Innovative Medicine, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Ling
authors.initials: L
authors.lastname: Han
authors.affiliation: Functional Proteomics, FIRC Institute of Molecular Oncology, Milan, Italy.|Protein Microsequencing Facility, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Cattaneo
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Consolato
authors.affiliation: Protein Microsequencing Facility, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Annapaola
authors.initials: A
authors.lastname: Andolfo
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Céline
authors.initials: C
authors.lastname: Schaeffer
authors.affiliation: Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Eric
authors.initials: E
authors.lastname: Olinger
authors.affiliation: Department of Molecular Cardiology, Lerner Research Institute, Cleveland, United States.
authors.forename: Jianhao
authors.initials: J
authors.lastname: Peng
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Santambrogio
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.
authors.forename: Romain
authors.initials: R
authors.lastname: Perrier
authors.affiliation: Department of Molecular Cardiology, Lerner Research Institute, Cleveland, United States.
authors.forename: Shuo
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Biosciences and Nutrition & Center for Innovative Medicine, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Marcel
authors.initials: M
authors.lastname: Bokhove
authors.affiliation: Functional Proteomics, FIRC Institute of Molecular Oncology, Milan, Italy.|Protein Microsequencing Facility, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Bachi
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.
authors.forename: Edith
authors.initials: E
authors.lastname: Hummler
authors.affiliation: Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Devuyst
authors.affiliation: Department of Molecular Cardiology, Lerner Research Institute, Cleveland, United States.
authors.forename: Qingyu
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Department of Biosciences and Nutrition & Center for Innovative Medicine, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Luca
authors.initials: L
authors.lastname: Jovine
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Rampoldi
mesh_terms: D000818:Animals; D002460:Cell Line; D004285:Dogs; D006801:Humans; D018345:Mice, Knockout; D055503:Protein Multimerization; D059748:Proteolysis; D012697:Serine Endopeptidases / Q000378:metabolism*; D058949:Uromodulin / Q000378:metabolism*
chemical_list: D058949:Uromodulin; D012697:Serine Endopeptidases; C055645:hepsin
keywords: Hepsin; Serine protease; Uromodulin; Zona Pellucida domain; biochemistry; cell biology; mouse