The deubiquitylase USP10 regulates integrin β1 and β5 and fibrotic wound healing

SR Gillespie, LJ Tedesco, L Wang… - Journal of Cell …, 2017 - journals.biologists.com
SR Gillespie, LJ Tedesco, L Wang, AM Bernstein
Journal of Cell Science, 2017journals.biologists.com
Scarring and fibrotic disease result from the persistence of myofibroblasts characterized by
high surface expression of αv integrins and subsequent activation of the transforming growth
factor β (TGFβ) proteins; however, the mechanism controlling their surface abundance is
unknown. Genetic screening revealed that human primary stromal corneal myofibroblasts
overexpress a subset of deubiquitylating enzymes (DUBs), which remove ubiquitin from
proteins, preventing degradation. Silencing of the DUB USP10 induces a buildup of …
Abstract
Scarring and fibrotic disease result from the persistence of myofibroblasts characterized by high surface expression of αv integrins and subsequent activation of the transforming growth factor β (TGFβ) proteins; however, the mechanism controlling their surface abundance is unknown. Genetic screening revealed that human primary stromal corneal myofibroblasts overexpress a subset of deubiquitylating enzymes (DUBs), which remove ubiquitin from proteins, preventing degradation. Silencing of the DUB USP10 induces a buildup of ubiquitin on integrins β1 and β5 in cell lysates, whereas recombinant USP10 removes ubiquitin from these integrin subunits. Correspondingly, the loss and gain of USP10 decreases and increases, respectively, αv/β1/β5 protein levels, without altering gene expression. Consequently, endogenous TGFβ is activated and the fibrotic markers alpha-smooth muscle actin (α-SMA) and cellular fibronectin (FN-EDA) are induced. Blocking either TGFβ signaling or cell-surface αv integrins after USP10 overexpression prevents or reduces fibrotic marker expression. Finally, silencing of USP10 in an ex vivo cornea organ culture model prevents the induction of fibrotic markers and promotes regenerative healing. This novel mechanism puts DUB expression at the head of a cascade regulating integrin abundance and suggests USP10 as a novel antifibrotic target.
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