Phosphatase PP2A is essential for TH17 differentiation

Qin Xu, Xuexiao Jin, Mingzhu Zheng, Deepak Rohila, Guotong Fu, Zhuoyu Wen, Jun Lou, Songquan Wu, Richard Sloan, Lie Wang, Hu Hu, Xiang Gao, Linrong Lu

Research output: Contribution to journalArticlepeer-review

Abstract

Phosphatase PP2A expression levels are positively correlated to the clinical severity of systemic lupus erythematosus (SLE) and IL17A cytokine overproduction, indicating a potential role of PP2A in controlling TH17 differentiation and inflammation. By generating a mouse strain with ablation of the catalytic subunit α of PP2A in peripheral mature T cells (PP2A cKO), we demonstrate that the PP2A complex is essential for TH17 differentiation. These PP2A cKO mice had reduced TH17 cell numbers and less severe disease in an experimental autoimmune encephalomyelitis (EAE) model. PP2A deficiency also ablated C-terminal phosphorylation of SMAD2 but increased C-terminal phosphorylation of SMAD3. By regulating the activity of RORγt via binding, the changes in the phosphorylation status of these R-SMADs reduced Il17a gene transcription. Finally, PP2A inhibitors showed similar effects on TH17 cells as were observed in PP2A cKO mice, i.e., decreased TH17 differentiation and relative protection of mice from EAE. Taken together, these data demonstrate that phosphatase PP2A is essential for TH17 differentiation and that inhibition of PP2A could be a possible therapeutic approach to controlling TH17-driven autoimmune diseases.

Original languageEnglish
Pages (from-to)982-987
Number of pages6
JournalProceedings of the National Academy of Sciences
Volume116
Issue number3
Early online date28 Dec 2018
DOIs
Publication statusPublished - 15 Jan 2019

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