The proteasome activator REGγ counteracts immunoproteasome expression and autoimmunity

For quite a long time, the 11S proteasome activator REGa and REG beta, but not REG gamma, are known to control immunoproteasome and promote antigen processing. Here, we demonstrate that REG gamma functions as an inhibitor for immunoproteasome and autoimmune disease. Depletion of REG gamma promotes MHC class I-restricted presentation to prime CD8(+) T cells in vitro and in vivo. Mice deficient for REG gamma have elevation of CD8(+) T cells and DCs, and develop age-related spontaneous autoimmune symptoms. Mechanistically, REG gamma 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 REG gamma. Importantly, treatment with STAT3 or LMP2/7 inhibitor prevented accumulation of immune complex in REG gamma(-/-) kidney. Moreover, REG gamma(-/-) mice also expedites Pristane-induced lupus. Bioinformatics and immunohistological analyses of clinical samples have correlated lower expression of REG gamma with enhanced expression of phosphorylated STAT3, LMP2 and LMP7 in human Lupus Nephritis. Collectively, our results support the concept that REG gamma is a new regulator of immunoproteasome to balance autoimmunity.