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Authors
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M.Brunati,
S.Perucca,
L.Han,
A.Cattaneo,
F.Consolato,
A.Andolfo,
C.Schaeffer,
E.Olinger,
J.Peng,
S.Santambrogio,
R.Perrier,
S.Li,
M.Bokhove,
A.Bachi,
E.Hummler,
O.Devuyst,
Q.Wu,
L.Jovine,
L.Rampoldi.
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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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