TY - JOUR

T1 - Matriptase zymogen supports epithelial development, homeostasis and regeneration

AU - Friis, Stine

AU - Tadeo, Daniel

AU - Le-Gall, Sylvain M.

AU - Jurgensen, Henrik Jessen

AU - Sales, Katiuchia Uzzun

AU - Camerer, Eric

AU - Bugge, Thomas H.

PY - 2017

Y1 - 2017

N2 - BackgroundMatriptase is a membrane serine protease essential for epithelial development, homeostasis, and regeneration, as well as a central orchestrator of pathogenic pericellular signaling in the context of inflammatory and proliferative diseases. Matriptase is an unusual protease in that its zymogen displays measurable enzymatic activity.ResultsHere, we used gain and loss of function genetics to investigate the possible biological functions of zymogen matriptase. Unexpectedly, transgenic mice mis-expressing a zymogen-locked version of matriptase in the epidermis displayed pathologies previously reported for transgenic mice mis-expressing wildtype epidermal matriptase. Equally surprising, mice engineered to express only zymogen-locked endogenous matriptase, unlike matriptase null mice, were viable, developed epithelial barrier function, and regenerated the injured epithelium. Compatible with these observations, wildtype and zymogen-locked matriptase were equipotent activators of PAR-2 inflammatory signaling.ConclusionThe study demonstrates that the matriptase zymogen is biologically active and is capable of executing developmental and homeostatic functions of the protease.

AB - BackgroundMatriptase is a membrane serine protease essential for epithelial development, homeostasis, and regeneration, as well as a central orchestrator of pathogenic pericellular signaling in the context of inflammatory and proliferative diseases. Matriptase is an unusual protease in that its zymogen displays measurable enzymatic activity.ResultsHere, we used gain and loss of function genetics to investigate the possible biological functions of zymogen matriptase. Unexpectedly, transgenic mice mis-expressing a zymogen-locked version of matriptase in the epidermis displayed pathologies previously reported for transgenic mice mis-expressing wildtype epidermal matriptase. Equally surprising, mice engineered to express only zymogen-locked endogenous matriptase, unlike matriptase null mice, were viable, developed epithelial barrier function, and regenerated the injured epithelium. Compatible with these observations, wildtype and zymogen-locked matriptase were equipotent activators of PAR-2 inflammatory signaling.ConclusionThe study demonstrates that the matriptase zymogen is biologically active and is capable of executing developmental and homeostatic functions of the protease.

KW - Development

KW - Cell surface proteolysis

KW - Epithelial cell signaling

KW - Zymogen activity

U2 - 10.1186/s12915-017-0384-4

DO - 10.1186/s12915-017-0384-4

M3 - Journal article

C2 - 28571576

VL - 15

JO - B M C Biology

JF - B M C Biology

SN - 1741-7007

M1 - 46

ER -