Phosphatases in lupus

Beth Israel Deaconess Medical Center, Boston MA

Investigators

Abstract

Systemic lupus erythematosus (SLE) presents profound T cell dysfunction and cytokine production. Decreased production of interleukin (IL)-2 and increased production of IL-17 contribute to compromised immune system homeostasis and the development of organ inflammation. Protein phosphatase 2A (PP2A), a trimolecular enzyme consisting of scaffolding, catalytic (c) and regulatory subunits, has been shown to control molecules involved in immune cell signaling and gene transcription resulting in suppression of the production of IL-2, enhancement of the production IL-17 and the generation of Treg and Th17 cells. PP2A has been recognized to contribute first to human SLE and later to murine lupus immunopathology. New preliminary experiments have revealed that PP2A controls in a direct manner the expression and function of distinct enzymes involved in glycolysis and the pentose phosphate pathway. The consorted effect of PP2A on these metabolic enzymes leads to compromised Treg function and poor control of the inflammatory response. This proposal will test the hypothesis PP2A controls the development and function of Treg cells by acting directly on intracellular enzymes involved in cell metabolism. In three sets of experiments, we will determine how PP2A controls the function of enzymes involved in the glycolysis and pentose phosphate pathway pathways; will establish that a PPP metabolite, gluconolactone can control inflammation and systemic autoimmunity in mice; and will establish that enzymes of the PPP are aberrantly expressed in people with SLE. The proposed work advances concepts whereby T cell function is regulated in an exact manner through the control of intracellular metabolic enzymes. The study will use mice with conditional deficiency of PP2A or PPP enzymes in Treg cells and normal or lupus-prone mice engineered to expressCas9-Gfp only in Treg cells. Advanced cell-targeted delivery of small drugs and gRNA will be used in Cas9 mice. The significance of the proposed work is with the identification of novel targets to control immune response homeostasis and is further affirmed with the discovery of metabolites which, when used either in vitro or in vivo, may control organ inflammation and autoimmunity.