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.

journal_name

Elife

journal_title

eLife

authors

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

doi

10.7554/eLife.08887

subject

Has Abstract

pub_date

2015-12-17 00:00:00

pages

e08887

issn

2050-084X

pii

08887

journal_volume

4

pub_type

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