The serine protease hepsin mediates urinary secretion and polymerisation of Zona Pellucida domain protein uromodulin
- San Raffaele Scientific Institute, Italy
- Karolinska Institutet, Sweden
- University of Zurich, Switzerland
- Lerner Research Institute, United States
- University of Lausanne, Switzerland
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.
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Animal experimentation: All animal studies were performed in strict adherence with the NIH Guide for the Care and Use of Laboratory Animals. Experimental procedures and animal maintenance at the University of Lausanne followed federal guidelines and were approved by local authorities (Service de la consommation et des affaires vétérinaires, authorization numbers 1003.7 and 25520 for animal experimentation, and VD-H06 for animal housing). Animal studies at the University of Zurich were performed under the approval of the Swiss Cantonal Veterinary Authority (Number: 103/2014). The protocol was approved by the Institutional Animal Care and Use Committee (IACUC) of the Cleveland Clinic (Number: 2015-1403).
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© 2015, Brunati et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The serine protease hepsin mediates urinary secretion and polymerisation of Zona Pellucida domain protein uromodulin
eLife 4:e08887.
https://doi.org/10.7554/eLife.08887
