The ER‐resident ubiquitin‐specific protease 19 participates in the UPR and rescues ERAD substrates

Abstract

Ubiquitination regulates membrane events such as endocytosis, membrane trafficking and endoplasmic-reticulum-associated degradation (ERAD). Although the involvement of membraneassociated ubiquitin-conjugating enzymes and ligases in these processes is well documented, their regulation by ubiquitin deconjugases is less well understood. By screening a database of human deubiquitinating enzymes (DUBs), we have identified a putative transmembrane domain in ubiquitin-specific protease (USP)19. We show that USP19 is a tail-anchored ubiquitin-specific protease localized to the ER and is a target of the unfolded protein response. USP19 rescues the ERAD substrates cystic fibrosis transmembrane conductance regulator (CFTR)DF508 and T-cell receptor-a (TCRa) from proteasomal degradation. A catalytically inactive USP19 was still able to partly rescue TCRa but not CFTRDF508, suggesting that USP19 might also exert a non-catalytic function on specific ERAD substrates. Thus, USP19 is the first example of a membrane-anchored DUB involved in the turnover of ERAD substrates.

17β-Estradiol Represses Myogenic Differentiation by Increasing Ubiquitin-specific Peptidase 19 through Estrogen Receptor α

“…To assess whether the inhibitory effect of USP19 on myogenesis is required for the deubiquitinating activity, mutant forms of USP19 lacking deubiquitinating activity were constructed, termed USP19(C548A) and USP19(C548S). These mutants replacing Ala and Ser for Cys at position 548 of USP19 are inactive (23). As shown in Fig.…”

Mechanisms of regulation and diversification of deubiquitylating enzyme function

“…This is especially evident in the case of the transmembrane DUBs USP19 and USP30 whose intracellular localization is highly restricted. Endoplasmic reticulum (ER) localization of USP19 is crucial for its function in the ERassociated degradation pathway (ERAD) (Hassink et al, 2009, but see also Lee et al, 2014, where USP19 involvement in ERAD has been questioned), secretion of misfolded proteins upon proteasome dysfunction and ER exit of membrane proteins that fold inefficiently (Perrody et al, 2016). Similarly, USP30, which is localized to the mitochondrial outer membrane, regulates mitochondrial morphology (Nakamura and Hirose, 2008) and has been implicated in Parkin-mediated mitophagy (Bingol et al, 2014;Liang et al, 2015).…”

Ubiquitin C-terminal Hydrolase-L1 Protects Cystic Fibrosis Transmembrane Conductance Regulator from Early Stages of Proteasomal Degradation

“…One DUB, Usp19, was recently demonstrated to stabilize several ERAD substrates including ⌬F508 CFTR (18). DUBs are responsible for counteracting the action of ubiquitination machinery through the cleavage of conjugated ubiquitin (19).…”