Opposing USP19 splice variants in TGF-β signaling and TGF-β-induced epithelial–mesenchymal transition of breast cancer cells

Abstract

Ubiquitin-specific protease (USP)19 is a deubiquitinating enzyme that regulates the stability and function of multiple proteins, thereby controlling various biological responses. The alternative splicing of USP19 results in the expression of two major encoded variants that are localized to the endoplasmic reticulum (ER) (USP19-ER) and cytoplasm (USP19-CY). The importance of alternative splicing for the function of USP19 remains unclear. Here, we demonstrated that USP19-CY promotes TGF-β signaling by directly interacting with TGF-β type I receptor (TβRI) and protecting it from degradation at the plasma membrane. In contrast, USP19-ER binds to and sequesters TβRI in the ER. By decreasing cell surface TβRI levels, USP19-ER inhibits TGF-β/SMAD signaling in a deubiquitination-independent manner. Moreover, USP19-ER inhibits TGF-β-induced epithelial–mesenchymal transition (EMT), whereas USP19-CY enhances EMT, as well as the migration and extravasation of breast cancer cells. Furthermore, USP19-CY expression is correlated with poor prognosis and is higher in breast cancer tissues than in adjacent normal tissues. Notably, the splicing modulator herboxidiene inhibits USP19-CY, increases USP19-ER expression and suppresses breast cancer cell migration. Targeting USP19 splicing or its deubiquitinating activity may have potential therapeutic effects on breast cancer.

Bicuspid Aortic Valve–Associated Regulatory Regions Reveal GATA4 Regulation and Function During Human-Induced Pluripotent Stem Cell–Based Endothelial-Mesenchymal Transition—Brief Report

“…Of note, TGFβ ligand is an essential factor of EndoMT and induces SERPINE1 expression, which is a molecular switch controlling cardiac TGFβ signaling. 29,30…”

ST3GAL5‐catalyzed gangliosides inhibit TGF‐β‐induced epithelial‐mesenchymal transition via TβRI degradation

“…To investigate the TGF‐β‐induced changes in GSL‐glycans in cells undergoing EMT, we chose two established cell models with prominent TGF‐β‐induced EMT responses, i.e., NMuMG (Zhang et al , 2020a) and A549‐vimentin (VIM)‐red fluorescent protein (RFP) cell lines (Wang et al , 2020). We performed quantitative glycomic analysis of these cell lines using porous graphitized carbon (PGC) nano‐liquid chromatography‐electrospray ionization tandem mass spectrometry (nano‐LC‐ESI‐MS/MS) in negative ESI mode, allowing in‐depth determination of GSL profiles (Appendix Fig S1; Anugraham et al , 2015).…”

“…Activation of EMT can endow cells with an enhanced ability to migrate (Zhang et al , 2020a). We thus further investigated the basal migration rate upon Ugcg KO in NMuMG cells.…”

Deubiquitinase USP19 modulates apoptotic calcium release and endoplasmic reticulum stress by deubiquitinating BAG6 in triple negative breast cancer

“…Even though there was evidence connecting USP19 to the progression of BC, only a handful of the underlying molecular pathways have been discussed. [11][12][13] ER is an important organelle responsible for protein processing, modification and folding, and plays a crucial role in cell Apoptosis. 14 Different oncogenic factors, as well as metabolic and transcriptional abnormalities in the tumor microenvironment cooperate to disrupt ER homeostasis and immune cell infiltration, which trigger a persistent state of ER stress.…”

“…found that C607S, an enzyme‐inactive mutant site of USP19 , failed to inhibit TNFA and IL‐1β‐triggered NF‐κB activation after mutation. Even though there was evidence connecting USP19 to the progression of BC, only a handful of the underlying molecular pathways have been discussed 11–13 …”