Mg 2+ regulation of kinase signaling and immune function.

Mg ²⁺ is required at micromolar concentrations as a cofactor for ATP, enzymatic reactions, and other biological processes. We show that decreased extracellular Mg ²⁺ reduced intracellular Mg ²⁺ levels and impaired the Ca ²⁺ flux, activation marker up-regulation, and proliferation after T cell receptor (TCR) stimulation. Reduced Mg ²⁺ specifically impairs TCR signal transduction by IL-2-inducible T cell kinase (ITK) due to a requirement for a regulatory Mg ²⁺ in the catalytic pocket of ITK. We also show that altered catalytic efficiency by millimolar changes in free basal Mg ²⁺ is an unrecognized but conserved feature of other serine/threonine and tyrosine kinases, suggesting a Mg ²⁺ regulatory paradigm of kinase function. Finally, a reduced serum Mg ²⁺ concentration in mice causes an impaired CD8 ⁺ T cell response to influenza A virus infection, reduces T cell activation, and exacerbates morbidity. Thus, Mg ²⁺ directly regulates the active site of specific kinases during T cell responses, and maintaining a high serum Mg ²⁺ concentration is important for antiviral immunity in otherwise healthy animals.
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