The deubiquitylase USP10 regulates integrin ?1 and ?5 and fibrotic wound healing.

ABSTRACT: Scarring and fibrotic disease result from the persistence of myofibroblasts characterized by high surface expression of ?v integrins and subsequent activation of the transforming growth factor ? (TGF?) 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 ?1 and ?5 in cell lysates, whereas recombinant USP10 removes ubiquitin from these integrin subunits. Correspondingly, the loss and gain of USP10 decreases and increases, respectively, ?v/?1/?5 protein levels, without altering gene expression. Consequently, endogenous TGF? is activated and the fibrotic markers alpha-smooth muscle actin (?-SMA) and cellular fibronectin (FN-EDA) are induced. Blocking either TGF? signaling or cell-surface ?v 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.

SUBMITTER: Gillespie SR 

PROVIDER: S-EPMC5665446 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature