Serine/threonine phosphatase PP2A is essential for optimal B cell function
Esra Meidan, Hao Li, Wenliang Pan, Michihito Kono, Shuilian Yu, Vasileios C. Kyttaris, Christina Ioannidis, Noe Rodriguez Rodriguez, Jose C. Crispin, Sokratis A. Apostolidis, Pui Lee, John Manis, Amir Sharabi, Maria G. Tsokos, George C. Tsokos
Esra Meidan, Hao Li, Wenliang Pan, Michihito Kono, Shuilian Yu, Vasileios C. Kyttaris, Christina Ioannidis, Noe Rodriguez Rodriguez, Jose C. Crispin, Sokratis A. Apostolidis, Pui Lee, John Manis, Amir Sharabi, Maria G. Tsokos, George C. Tsokos
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Research Article Immunology

Serine/threonine phosphatase PP2A is essential for optimal B cell function

Abstract

Protein phosphatase 2A (PP2A), a serine/threonine phosphatase, has been shown to control T cell function. We found that in vitro–activated B cells and B cells from various lupus-prone mice and patients with systemic lupus erythematosus display increased PP2A activity. To understand the contribution of PP2A to B cell function, we generated a Cd19CrePpp2r1afl/fl (flox/flox) mouse which lacks functional PP2A only in B cells. Flox/flox mice displayed reduced spontaneous germinal center formation and decreased responses to T cell-dependent and T-independent antigens, while their B cells responded poorly in vitro to stimulation with an anti-CD40 antibody or CpG in the presence of IL-4. Transcriptome and metabolome studies revealed altered nicotinamide adenine dinucleotide (NAD) and purine/pyrimidine metabolism and increased expression of purine nucleoside phosphorylase in PP2A-deficient B cells. Our results demonstrate that PP2A is required for optimal B cell function and may contribute to increased B cell activity in systemic autoimmunity.

Authors

Esra Meidan, Hao Li, Wenliang Pan, Michihito Kono, Shuilian Yu, Vasileios C. Kyttaris, Christina Ioannidis, Noe Rodriguez Rodriguez, Jose C. Crispin, Sokratis A. Apostolidis, Pui Lee, John Manis, Amir Sharabi, Maria G. Tsokos, George C. Tsokos

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Figure 5

PP2A in B cells inhibits mitochondrial respiration by suppressing the expression of purine nucleoside phosphorylase (PNP).

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PP2A in B cells inhibits mitochondrial respiration by suppressing the ex...
(A) Dot plots show mitochondrial respiration in Ppp2r1a-deficient mouse splenic B cells compared with WT mouse splenic B cells (maximal oxygen consumption rate [OCR]and space capacity OCR) (n = 4 independent experiments). (B) Joint analysis of RNA sequencing and metabolomics in B cells from flox/flox mice compared with control mice (n = 3 mice per group). (C) Increased PNP mRNA expression in B cells from flox/flox mice compared with control mice (n = 6 mice per group for qPCR experiment). (D) Western blot analysis on PNP expression in mouse splenic B cells with PP2Aa deficiency compared with WT controls. Quantification of Western blots. (E) Human primary B cells were enriched from peripheral blood mononuclear cells (PBMC). Left: Representation of oxygen consumption rate (OCR) of human primary B cells exposed to the indicated treatments (9-Deazaguanine was applied as PNP inhibitor). Right: Dot plots indicate mitochondrial respiration in human primary B cells with PP2Aa deficiency compared with controls exposed to the indicated treatments. Paired t test, mean ± SEM.