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Sci. Signal., 10 February 2009
Vol. 2, Issue 57, p. ra5
[DOI: 10.1126/scisignal.2000081]

RESEARCH ARTICLES

Brx Mediates the Response of Lymphocytes to Osmotic Stress Through the Activation of NFAT5

Tomoshige Kino1*, Hiroaki Takatori2, Irini Manoli3,4, Yonghong Wang5, Anatoly Tiulpakov1, Marc R. Blackman3,6, Yan A. Su7, George P. Chrousos1,4, Alan H. DeCherney1, and James H. Segars1

1 Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
2 Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
3 Endocrine Section, Laboratory of Clinical Investigation, National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, MD 20892, USA.
4 First Department of Pediatrics, Athens University, Athens 11527, Greece.
5 Clinical Molecular Profiling Core, Advanced Technology Center, National Cancer Institute, National Institutes of Health, Gaithersburg, MD 20892, USA.
6 Washington DC VA Medical Center, Washington, DC 20422, USA.
7 Department of Biochemistry and Molecular Biology, the Catherine Birch McCormick Genomics Center, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.

Abstract: Extracellular hyperosmolarity, or osmotic stress, generally caused by differences in salt and macromolecule concentrations across the plasma membrane, occurs in lymphoid organs and at inflammatory sites. The response of immune cells to osmotic stress is regulated by nuclear factor of activated T cells 5 (NFAT5), a transcription factor that induces the expression of hyperosmolarity-responsive genes and stimulates cytokine production. We report that the guanine nucleotide exchange factor (GEF) Brx [also known as protein kinase A–anchoring protein 13 (AKAP13)] is essential for the expression of nfat5 in response to osmotic stress, thus transmitting the extracellular hyperosmolarity signal and enabling differentiation of splenic B cells and production of immunoglobulin. This process required the activity of p38 mitogen-activated protein kinase (MAPK) and NFAT5 and involved a physical interaction between Brx and c-Jun N-terminal kinase (JNK)–interacting protein 4 (JIP4), a scaffold molecule specific to activation of the p38 MAPK cascade. Our results indicate that Brx integrates the responses of immune cells to osmotic stress and inflammation by elevating intracellular osmolarity and stimulating the production of cytokines.

* To whom correspondence should be addressed. E-mail: kinot{at}mail.nih.gov

Citation: T. Kino, H. Takatori, I. Manoli, Y. Wang, A. Tiulpakov, M. R. Blackman, Y. A. Su, G. P. Chrousos, A. H. DeCherney, J. H. Segars, Brx Mediates the Response of Lymphocytes to Osmotic Stress Through the Activation of NFAT5. Sci. Signal. 2, ra5 (2009).

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