The serine protease hepsin mediates urinary secretion and polymerisation of Zona Pellucida domain protein uromodulin
| العنوان: | The serine protease hepsin mediates urinary secretion and polymerisation of Zona Pellucida domain protein uromodulin |
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| المؤلفون: | Sara Santambrogio, Angela Bachi, Annapaola Andolfo, Olivier Devuyst, Martina Brunati, Francesco Consolato, Céline Schaeffer, Romain Perrier, Marcel Bokhove, Angela Cattaneo, Luca Jovine, Simone Perucca, Edith Hummler, Shuo Li, Jianhao Peng, Qingyu Wu, Luca Rampoldi, Eric Olinger, Ling Han |
| المساهمون: | University of Zurich, Rampoldi, Luca, Brunati, M, Perucca, S, Han, L, Cattaneo, A, Consolato, F, Andolfo, A, Schaeffer, C, Olinger, E, Peng, Jh, Santambrogio, S, Perrier, R, Li, S, Bokhove, M, Bachi, A, Hummler, E, Devuyst, O, Wu, Qy, Jovine, L, Rampoldi, L |
| المصدر: | eLife eLife, Vol 4 (2015) Europe PubMed Central Elife, vol. 4, pp. e08887 |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | Tamm–Horsfall protein, Mouse, QH301-705.5, Science, Hepsin, Protein domain, Zona Pellucida domain, 610 Medicine & health, Biochemistry, General Biochemistry, Genetics and Molecular Biology, 10052 Institute of Physiology, Cell Line, Cell membrane, Dogs, 1300 General Biochemistry, Genetics and Molecular Biology, 2400 General Immunology and Microbiology, Uromodulin, medicine, Animals, Humans, Secretion, Biology (General), Zona pellucida, Serine protease, Mice, Knockout, General Immunology and Microbiology, biology, General Neuroscience, Serine Endopeptidases, 2800 General Neuroscience, General Medicine, Cell Biology, 3. Good health, medicine.anatomical_structure, 10076 Center for Integrative Human Physiology, Proteolysis, biology.protein, Serine Protease Hepsin, 570 Life sciences, Medicine, Protein Multimerization, Research Article |
| الوصف: | 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. DOI: http://dx.doi.org/10.7554/eLife.08887.001Test eLife digest Several proteins in humans and other animals contain a region called a 'zona pellucida domain'. This domain enables these proteins to associate with each other and form long filaments. Uromodulin is one such protein that was first identified more than fifty years ago. This protein is known to play a role in human diseases such as hypertension and kidney failure, but uromodulin’s biological purpose still remains elusive. Uromodulin is only made in the kidney and it is the most abundant protein in the urine of healthy individuals. Uromodulin also contains a so-called 'external hydrophobic patch' that must be removed before the zona pellucida domain can start to form filaments. This hydrophobic patch is removed when uromodulin is cut by an unknown enzyme; this cutting releases the rest of the uromodulin protein from the surface of the cells that line the kidney into the urine. Brunati et al. have now tested a panel of candidate enzymes and identified that one called hepsin is able to cut uromodulin. Hepsin is embedded in the cell membrane of the cells that line the kidney. When the level of hepsin was artificially reduced in cells grown in the laboratory, uromodulin remained anchored to the cell surface, its processing was altered and it did not form filaments. Brunati et al. next analysed mice in which the gene encoding hepsin had been deleted. While these animals did not have any major defects in their internal organs, they had much lower levels of uromodulin in their urine. Furthermore, this residual urinary protein was not cut properly and it did not assemble into filaments. Thus, these findings reveal that hepsin is the enzyme that is responsible for releasing uromodulin in the urine. This discovery could be exploited to alter the levels of uromodulin release, and further studies using mice lacking hepsin may also help to understand uromodulin’s biological role. Finally, it will be important to understand if hepsin, or a similar enzyme, is also responsible for the release of other proteins containing the zona pellucida domain. DOI: http://dx.doi.org/10.7554/eLife.08887.002Test |
| وصف الملف: | elife-08887-v2.pdf - application/pdf; application/pdf |
| تدمد: | 2050-084X |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c55c6546788add11fb5242206dca3674Test https://pubmed.ncbi.nlm.nih.gov/26673890Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....c55c6546788add11fb5242206dca3674 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 2050084X |
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