Signalling to transcription: store-operated Ca2+ entry and NFAT activation in lymphocytes.
In cells of the immune system that are stimulated by antigen or antigen-antibody complexes, Ca(2+) entry from the extracellular medium is driven by depletion of endoplasmic reticulum Ca(2+) stores and occurs through specialized store-operated Ca(2+) channels known as Ca(2+)-release-activated Ca(2+) (CRAC) channels. The process of store-operated Ca(2+) influx is essential for short-term as well as long-term responses by immune-system cells. Short-term responses include mast cell degranulation and killing of target cells by effector cytolytic T cells, whereas long-term responses typically involve changes in gene transcription and include T and B cell proliferation and differentiation. Transcription downstream of Ca(2+) influx is in large part funneled through the transcription factor nuclear factor of activated T cells (NFAT), a heavily phosphorylated protein that is cytoplasmic in resting cells, but that enters the nucleus when dephosphorylated by the calmodulin-dependent serine/threonine phosphatase calcineurin. The importance of the Ca(2+)/calcineurin/NFAT signalling pathway for lymphocyte activation is underscored by the finding that the underlying defect in a family with a hereditary severe combined immune deficiency (SCID) syndrome is a defect in CRAC channel function, store-operated Ca(2+) entry, NFAT activation and transcription of cytokines, chemokines and many other NFAT target genes whose transcription is essential for productive immune defence. We recently used a two-pronged genetic approach to identify Orai1 as the pore subunit of the CRAC channel. On the one hand, we initiated a positional cloning approach in which we utilised genome-wide single nucleotide polymorphism (SNP) mapping to identify the genomic region linked to the mutant gene in the SCID family described above. In parallel, we used a genome-wide RNAi screen in Drosophila to identify critical regulators of NFAT nuclear translocation and store-operated Ca(2+) entry. These approaches, together with subsequent mutational and electrophysiological analyses, converged to identify human Orai1 as a pore subunit of the CRAC channel and as the gene product mutated in the SCID patients.
Gwack
Yousang
Y
Department of Pathology, Harvard Medical School, The CBR Institute for Biomedical Research, 200 Longwood Avenue, Boston, MA 02115, USA.
Feske
Stefan
S
Srikanth
Sonal
S
Hogan
Patrick G
PG
Rao
Anjana
A
D000818:Animals; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling; D006801:Humans; D008214:Lymphocytes / Q000276:immunology*; D008407:Mast Cells / Q000276:immunology; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics; D050778:NFATC Transcription Factors / Q000378:metabolism*; D000071740:ORAI1 Protein; D016511:Severe Combined Immunodeficiency / Q000235:genetics; D015533:Transcriptional Activation
D015220:Calcium Channels; D008565:Membrane Proteins; D050778:NFATC Transcription Factors; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; D002118:Calcium