| First Author | Yao L | Year | 2019 |
| Journal | J Autoimmun | Volume | 103 |
| Pages | 102282 | PubMed ID | 31171475 |
| Mgi Jnum | J:293514 | Mgi Id | MGI:6452881 |
| Doi | 10.1016/j.jaut.2019.05.010 | Citation | Yao L, et al. (2019) The proteasome activator REGgamma counteracts immunoproteasome expression and autoimmunity. J Autoimmun 103:102282 |
| abstractText | For quite a long time, the 11S proteasome activator REGa and REGbeta, but not REGgamma, are known to control immunoproteasome and promote antigen processing. Here, we demonstrate that REGgamma functions as an inhibitor for immunoproteasome and autoimmune disease. Depletion of REGgamma promotes MHC class I-restricted presentation to prime CD8(+) T cells in vitro and in vivo. Mice deficient for REGgamma have elevation of CD8(+) T cells and DCs, and develop age-related spontaneous autoimmune symptoms. Mechanistically, REGgamma specifically interacts with phosphorylated STAT3 and promotes its degradation in vitro and in cells. Inhibition of STAT3 dramatically attenuates levels of LMP2/LMP7 and antigen presentation in cells lacking REGgamma. Importantly, treatment with STAT3 or LMP2/7 inhibitor prevented accumulation of immune complex in REGgamma(-/-) kidney. Moreover, REGgamma(-/-) mice also expedites Pristane-induced lupus. Bioinformatics and immunohistological analyses of clinical samples have correlated lower expression of REGgamma with enhanced expression of phosphorylated STAT3, LMP2 and LMP7 in human Lupus Nephritis. Collectively, our results support the concept that REGgamma is a new regulator of immunoproteasome to balance autoimmunity. |
