The serine protease hepsin mediates urinary secretion and polymerisation of zona pellucida domain protein uromodulin

Martina Brunati, Simone Perucca, Ling Han, Angela Cattaneo, Francesco Consolato, Annapaola Andolfo, Céline Schaeffer, Eric Olinger, Jianhao Peng, Sara Santambrogio, Romain Perrier, Shuo Li, Marcel Bokhove, Angela Bachi, Edith Hummler, Olivier Devuyst, Qingyu Wu, Luca Jovine, Luca Rampoldi

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article numbere08887
JournaleLife
Volume4
Issue numberDECEMBER2015
DOIs
Publication statusPublished - Dec 17 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Medicine(all)
  • Neuroscience(all)

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  • Cite this

    Brunati, M., Perucca, S., Han, L., Cattaneo, A., Consolato, F., Andolfo, A., Schaeffer, C., Olinger, E., Peng, J., Santambrogio, S., Perrier, R., Li, S., Bokhove, M., Bachi, A., Hummler, E., Devuyst, O., Wu, Q., Jovine, L., & Rampoldi, L. (2015). The serine protease hepsin mediates urinary secretion and polymerisation of zona pellucida domain protein uromodulin. eLife, 4(DECEMBER2015), [e08887]. https://doi.org/10.7554/eLife.08887