Brx mediates the response of lymphocytes to osmotic stress through the activation of NFAT5.
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.
Kino
Tomoshige
T
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. kinot@mail.nih.gov
Takatori
Hiroaki
H
Manoli
Irini
I
Wang
Yonghong
Y
Tiulpakov
Anatoly
A
Blackman
Marc R
MR
Su
Yan A
YA
Chrousos
George P
GP
DeCherney
Alan H
AH
Segars
James H
JH
D054758:A Kinase Anchor Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D053264:B-Cell Activating Factor / Q000097:blood; D001402:B-Lymphocytes / Q000276:immunology; D003681:Dehydration; D005786:Gene Expression Regulation; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis; D008214:Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D009997:Osmotic Pressure; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D013154:Spleen / Q000033:anatomy & histology / Q000201:enzymology / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D054758:A Kinase Anchor Proteins; C085467:AKAP13 protein, human; D053264:B-Cell Activating Factor; D007136:Immunoglobulins; D015778:Minor Histocompatibility Antigens; C118125:NFAT5 protein, human; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C505720:Tnfsf13b protein, mouse; D014157:Transcription Factors; D011505:Protein-Tyrosine Kinases