The proteasome activator REGγ counteracts immunoproteasome expression and autoimmunity

Liangfang Yao, Lei Zhou, Yang Xuan, Pei Zhang, Xiaoshuang Wang, Tianzhen Wang, Tianyuan Meng, Yanyan Xue, Xueqing Ma, Abdus Saboor Shah, Shiwang Shang, Xinglong Ma, Wei Xie, Hao Wang, Qing Fu, Yanyang Xia, Robb Moses, Hongyan Wang, Lei Li, Jianru XiaoBianhong Zhang, Xiaotao Li

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

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

Original languageEnglish (US)
Article number102282
JournalJournal of Autoimmunity
Volume103
DOIs
StatePublished - Sep 1 2019

Keywords

  • Autoimmunity
  • LMP2(7)
  • Phosphorylated STAT3
  • REGγ

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Yao, L., Zhou, L., Xuan, Y., Zhang, P., Wang, X., Wang, T., Meng, T., Xue, Y., Ma, X., Shah, A. S., Shang, S., Ma, X., Xie, W., Wang, H., Fu, Q., Xia, Y., Moses, R., Wang, H., Li, L., ... Li, X. (2019). The proteasome activator REGγ counteracts immunoproteasome expression and autoimmunity. Journal of Autoimmunity, 103, [102282]. https://doi.org/10.1016/j.jaut.2019.05.010