Protein Phosphatase 2A Enables Expression of Interleukin 17 (IL-17) through Chromatin Remodeling
Year: 2013
Type: article
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. Background: Increased PP2A levels have been linked to autoimmunity in SLE patients and transgenic mice. Results: In T cells, PP2A overexpression increases the transcription of proinflammatory genes and facilitates chromatin accessibility at the Il17 locus. Conclusion: Increased levels of PP2A promote the inflammatory capacity of T cells. Significance: PP2A dysregulation may contribute to SLE by directly affecting lymphocyte gene expression.
Source: Journal of Biological Chemistry
Institutions: Beth Israel Deaconess Medical Center, Harvard University
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
Award: Phosphatases in human lupus
OpenAlex ID: W2038119991