title: Second messenger role for Mg2+ revealed by human T-cell immunodeficiency.
abstract: The magnesium ion, Mg(2+), is essential for all life as a cofactor for ATP, polyphosphates such as DNA and RNA, and metabolic enzymes, but whether it plays a part in intracellular signalling (as Ca(2+) does) is unknown. Here we identify mutations in the magnesium transporter gene, MAGT1, in a novel X-linked human immunodeficiency characterized by CD4 lymphopenia, severe chronic viral infections, and defective T-lymphocyte activation. We demonstrate that a rapid transient Mg(2+) influx is induced by antigen receptor stimulation in normal T cells and by growth factor stimulation in non-lymphoid cells. MAGT1 deficiency abrogates the Mg(2+) influx, leading to impaired responses to antigen receptor engagement, including defective activation of phospholipase Cγ1 and a markedly impaired Ca(2+) influx in T cells but not B cells. These observations reveal a role for Mg(2+) as an intracellular second messenger coupling cell-surface receptor activation to intracellular effectors and identify MAGT1 as a possible target for novel therapeutics.
authors.affiliation: Molecular Development Section, Lymphocyte Molecular Genetics Unit, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Feng-Yen
authors.initials: FY
authors.lastname: Li
authors.forename: Benjamin
authors.initials: B
authors.lastname: Chaigne-Delalande
authors.forename: Chrysi
authors.initials: C
authors.lastname: Kanellopoulou
authors.forename: Jeremiah C
authors.initials: JC
authors.lastname: Davis
authors.forename: Helen F
authors.initials: HF
authors.lastname: Matthews
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
authors.forename: Jeffrey I
authors.initials: JI
authors.lastname: Cohen
authors.forename: Gulbu
authors.initials: G
authors.lastname: Uzel
authors.forename: Helen C
authors.initials: HC
authors.lastname: Su
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lenardo
mesh_terms: D002118:Calcium / Q000276:immunology; D027682:Cation Transport Proteins / Q000235:genetics; D005260:Female; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D008274:Magnesium / Q000276:immunology*; D008297:Male; D051966:Phospholipase C gamma / Q000235:genetics / Q000378:metabolism; D015290:Second Messenger Systems / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D018344:T-Lymphocytopenia, Idiopathic CD4-Positive / Q000235:genetics / Q000276:immunology*
chemical_list: D027682:Cation Transport Proteins; C509698:MagT1 protein, human; D051966:Phospholipase C gamma; D008274:Magnesium; D002118:Calcium