The catalytic subunit of protein phosphatase 2A (PP2Ac) promotes DNA hypomethylation by suppressing the phosphorylated mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/phosphorylated ERK/DNMT1 protein pathway in T-cells from controls and systemic lupus erythematosus patients.

ABSTRACT

DNA hypomethylation is a characteristic feature of systemic lupus erythematosus (SLE) immune cells. Numerous reports have implicated the involvement of the MEK/ERK pathway in the reduction of DNA methyltransferase (DNMT) expression, hence inducing the transcription of methylation-sensitive genes in SLE patients. However, the molecular mechanisms involved remain unclear. Here, we investigated whether the catalytic subunit of protein phosphatase 2A (PP2Ac), which is overexpressed in SLE T-cells, contributes to reduced DNA methylation. We show that both chemical suppression and siRNA silencing of PP2Ac in T-cells resulted in sustained phosphorylation of MEK and ERK following stimulation with phorbol 12-myristate 13-acetate and ionomycin. Furthermore, PP2Ac suppression resulted in increased DNMT enzyme activity, DNA hypermethylation, and decreased expression of methylation-sensitive genes. Similarly, in SLE T-cells, suppression of PP2Ac resulted in increased MEK/ERK phosphorylation, enhanced DNMT1 expression and suppressed expression of the methylation-sensitive CD70 gene. Our results demonstrate that PP2A regulates DNA methylation by influencing the phosphorylation of MEK/ERK. We propose that enhanced PP2Ac in SLE T-cells may dephosphorylate and activate the signaling pathway upstream of DNMT1, thus disturbing the tight control of methylation-sensitive genes, which are involved in SLE pathogenesis.