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About the Authors:
Muhammad S. Alam
Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing - original draft
Affiliation: Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
Matthias M. Gaida
Roles Investigation
Affiliations Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
Subrata Debnath
Roles Investigation
Affiliation: Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
Harichandra D. Tagad
Roles Investigation
Affiliation: Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
Lisa M. Miller Jenkins
Roles Investigation
Affiliation: Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
Ettore Appella
Roles Supervision
Affiliation: Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
M. Jubayer Rahman
Roles Investigation
Affiliation: Laboratory of Molecular Immunology at the Immunology Center, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, Maryland, United States of America
Jonathan D. Ashwell
Roles Conceptualization, Formal analysis, Methodology, Project administration, Resources, Supervision, Writing - review & editing
* E-mail: [email protected]
Affiliation: Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
ORCID http://orcid.org/0000-0002-7386-8738Abstract
Nuclear factor of activated T cells (NFAT) transcription factors are required for induction of T-cell cytokine production and effector function. Although it is known that activation via the T-cell antigen receptor (TCR) results in 2 critical steps, calcineurin-mediated NFAT1 dephosphorylation and NFAT2 up-regulation, the molecular mechanisms underlying each are poorly understood. Here we find that T cell p38, which is activated by an alternative pathway independent of the mitogen-activated protein (MAP) kinase cascade and with different substrate specificities, directly controls these events. First, alternatively (but not classically) activated p38 was required to induce the expression of the AP-1 component c-Fos, which was necessary for NFAT2 expression and cytokine production. Second, alternatively (but not classically) activated p38 phosphorylated NFAT1 on a heretofore unidentified site, S79, and in its absence NFAT1 was unable to interact with calcineurin or migrate to the nucleus....