title: Protein phosphatase 2A enables expression of interleukin 17 (IL-17) through chromatin remodeling.
abstract: Protein phosphatase 2A (PP2A) is a heterotrimeric serine/threonine phosphatase involved in essential cellular functions. T cells from patients with systemic lupus erythematosus (SLE) express high levels of the catalytic subunit of PP2A (PP2Ac). A mouse overexpressing PP2Ac in T cells develops glomerulonephritis in an IL-17-dependent manner. Here, using microarray analyses, we demonstrate that increased expression of PP2Ac grants T cells the capacity to produce an array of proinflammatory effector molecules. Because IL-17 is important in the expression of glomerulonephritis, we studied the mechanism through which PP2Ac dysregulation facilitates its production. We report that PP2Ac is involved in the regulation of the Il17 locus by enhancing histone 3 acetylation through a mechanism that involves activation of interferon regulatory factor 4. Increased histone 3 acetylation of the Il17 locus is shared between T cells of PP2Ac transgenic mice and patients with SLE. We propose that, by promoting the inflammatory capacity of T cells, PP2Ac dysregulation contributes to the pathogenesis of SLE.
authors.affiliation: From the Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215.
authors.forename: Sokratis A
authors.initials: SA
authors.lastname: Apostolidis
authors.forename: Thomas
authors.initials: T
authors.lastname: Rauen
authors.forename: Christian M
authors.initials: CM
authors.lastname: Hedrich
authors.forename: George C
authors.initials: GC
authors.lastname: Tsokos
authors.forename: José C
authors.initials: JC
authors.lastname: Crispín
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D002843:Chromatin / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly / Q000502:physiology*; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D007249:Inflammation; D020381:Interleukin-17 / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000201:enzymology / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D002843:Chromatin; D006657:Histones; D020381:Interleukin-17; D054460:rho-Associated Kinases; C578496:PPP2CA protein, mouse; D054648:Protein Phosphatase 2
keywords: Autoimmunity; Chromatin Histone Modification; Inflammation; Interleukin; PP2A; T Cell
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