The serine/threonine protein phosphatase 2A controls autoimmunity

Abstract

Protein phosphatase 2A (PP2A) is the first serine/threonine phosphatase recognized to contribute to human and murine lupus immunopathology. PP2A expression in SLE is controlled both epigenetically and genetically, and it is increased in patients with SLE, which contributes to decreased IL-2 production, decreased CD3ζ and increased FcRγ expression on the surface of T cells, increased CREMα expression, hypomethylation of genes associated with SLE pathogenesis, and increased IL-17 production. β regulatory subunit of PP2A regulates IL-2 deprivation-induced T cell death and is decreased in SLE patients. A mouse overexpressing PP2A_c in T cells displays peripheral granulocytosis, elevated IL-17 production, and develops glomerulonephritis when challenged. A mouse which lacks PP2A_c only in regulatory T cells develops severe autoimmunity and multiorgan inflammation because of loss of restraint on mTORC1 and inability of Foxp3+ cells to regulate conventional T cells. Targeting PP2A in T cell subsets may be therapeutic for SLE and other autoimmune diseases.

Figure 1

Schematic structure of protein phosphatase 2A (PP2A). It is composed of three hetero-dimers, the scaffold subunit, the catalytic subunit, and the regulatory subunit (depicted as A, C, and B, respectively). There are four families of regulatory subunits, each having multiple isoforms as shown in the figure.

Figure 2

Single nucleotide polymorphism (SNP) in PP2A from SLE T cells impairs the binding of repressor transcription factor Ikaros. A schematic representation of the gene IKZF1, wherein the green boxes represent the introns, and the red letters the sequence of the variant site to which Ikaros binding is impaired resulting in less histone deacetylase HDAC1 recruitment, and less suppression of PP2A transcription.

Figure 3

CD3ζ - and FcRγ chains are components of CD3/TCR complex, and the transcription factor Elf-1 affects them antithetically. The increased PP2A_c activity results in Elf-1 dephosphorylation, and impairs Elf-1 binding to the CD3ζ and FcRγ promoters suppressing and enhancing their transcriptional activity respectively.

Figure 4

PP2A controls a number of pathways in the SLE T cell.

Figure 5

T_reg cells inhibit mTO RC1 through ceramide-mediated activation of PP2A. PC: Phosphatidylcholine, DAG: diacyl-glycerol.