Mg2+ regulation of kinase signaling and immune function

Mg2+ is required at micromolar concentrations as a cofactor for ATP, enzymatic reactions, and other biological processes. We show that decreased extracellular Mg2+ reduced intracellular Mg2+ levels and impaired the Ca2+ flux, activation marker up-regulation, and proliferation after T cell receptor (TCR) stimulation. Reduced Mg2+ specifically impairs TCR signal transduction by IL-2–inducible T cell kinase (ITK) due to a requirement for a regulatory Mg2+ in the catalytic pocket of ITK. We also show that altered catalytic efficiency by millimolar changes in free basal Mg2+ is an unrecognized but conserved feature of other serine/threonine and tyrosine kinases, suggesting a Mg2+ regulatory paradigm of kinase function. Finally, a reduced serum Mg2+ concentration in mice causes an impaired CD8+ T cell response to influenza A virus infection, reduces T cell activation, and exacerbates morbidity. Thus, Mg2+ directly regulates the active site of specific kinases during T cell responses, and maintaining a high serum Mg2+ concentration is important for antiviral immunity in otherwise healthy animals.

Source: The Journal of Experimental Medicine - August 4, 2019 Category: Internal Medicine Authors: Kanellopoulou, C., George, A. B., Masutani, E., Cannons, J. L., Ravell, J. C., Yamamoto, T. N., Smelkinson, M. G., Jiang, P. D., Matsuda-Lennikov, M., Reilley, J., Handon, R., Lee, P.-H., Miller, J. R., Restifo, N. P., Zheng, L., Schwartzberg, P. L., Youn Tags: Infectious Disease and Host Defense Articles Source Type: research