Second messenger role for Mg2+ revealed by human T-cell immunodeficiency

Feng-Yen Li, Benjamin Chaigne-Delalande, Chrysi Kanellopoulou, Jeremiah C. Davis, Helen F. Matthews, Daniel C. Douek, Jeffrey I. Cohen, Gulbu Uzel, Helen C. Su and Michael J. Lenardo ()
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Feng-Yen Li: Molecular Development Section, Lymphocyte Molecular Genetics Unit, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Benjamin Chaigne-Delalande: Molecular Development Section, Lymphocyte Molecular Genetics Unit, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Chrysi Kanellopoulou: Molecular Development Section, Lymphocyte Molecular Genetics Unit, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Jeremiah C. Davis: Human Immunological Diseases Unit, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Helen F. Matthews: Molecular Development Section, Lymphocyte Molecular Genetics Unit, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Daniel C. Douek: Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Jeffrey I. Cohen: Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Gulbu Uzel: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Helen C. Su: Human Immunological Diseases Unit, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Michael J. Lenardo: Molecular Development Section, Lymphocyte Molecular Genetics Unit, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health

Nature, 2011, vol. 475, issue 7357, 471-476

Abstract: Abstract The magnesium ion, Mg2+, 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 Ca2+ 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 Mg2+ influx is induced by antigen receptor stimulation in normal T cells and by growth factor stimulation in non-lymphoid cells. MAGT1 deficiency abrogates the Mg2+ influx, leading to impaired responses to antigen receptor engagement, including defective activation of phospholipase Cγ1 and a markedly impaired Ca2+ influx in T cells but not B cells. These observations reveal a role for Mg2+ as an intracellular second messenger coupling cell-surface receptor activation to intracellular effectors and identify MAGT1 as a possible target for novel therapeutics.

Date: 2011
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DOI: 10.1038/nature10246

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