| First Author | Jean-Charles PY | Year | 2016 |
| Journal | J Biol Chem | Volume | 291 |
| Issue | 14 | Pages | 7450-64 |
| PubMed ID | 26839314 | Mgi Jnum | J:232730 |
| Mgi Id | MGI:5780002 | Doi | 10.1074/jbc.M115.687129 |
| Citation | Jean-Charles PY, et al. (2016) Ubiquitin-specific Protease 20 Regulates the Reciprocal Functions of beta-Arrestin2 in Toll-like Receptor 4-promoted Nuclear Factor kappaB (NFkappaB) Activation. J Biol Chem 291(14):7450-64 |
| abstractText | Toll-like receptor 4 (TLR4) promotes vascular inflammatory disorders such as neointimal hyperplasia and atherosclerosis. TLR4 triggers NFkappaB signaling through the ubiquitin ligase TRAF6 (tumor necrosis factor receptor-associated factor 6). TRAF6 activity can be impeded by deubiquitinating enzymes like ubiquitin-specific protease 20 (USP20), which can reverse TRAF6 autoubiquitination, and by association with the multifunctional adaptor protein beta-arrestin2. Although beta-arrestin2 effects on TRAF6 suggest an anti-inflammatory role, physiologic beta-arrestin2 promotes inflammation in atherosclerosis and neointimal hyperplasia. We hypothesized that anti- and proinflammatory dimensions of beta-arrestin2 activity could be dictated by beta-arrestin2's ubiquitination status, which has been linked with its ability to scaffold and localize activated ERK1/2 to signalosomes. With purified proteins and in intact cells, our protein interaction studies showed that TRAF6/USP20 association and subsequent USP20-mediated TRAF6 deubiquitination were beta-arrestin2-dependent. Generation of transgenic mice with smooth muscle cell-specific expression of either USP20 or its catalytically inactive mutant revealed anti-inflammatory effects of USP20in vivoandin vitro Carotid endothelial denudation showed that antagonizing smooth muscle cell USP20 activity increased NFkappaB activation and neointimal hyperplasia. We found that beta-arrestin2 ubiquitination was promoted by TLR4 and reversed by USP20. The association of USP20 with beta-arrestin2 was augmented when beta-arrestin2 ubiquitination was prevented and reduced when beta-arrestin2 ubiquitination was rendered constitutive. Constitutive beta-arrestin2 ubiquitination also augmented NFkappaB activation. We infer that pro- and anti-inflammatory activities of beta-arrestin2 are determined by beta-arrestin2 ubiquitination and that changes in USP20 expression and/or activity can therefore regulate inflammatory responses, at least in part, by defining the ubiquitination status of beta-arrestin2. |
