Unique properties of TCR-activated p38 are necessary for NFAT-dependent T-cell activation

• Published in: PLoS biology 2018-01, Vol.16 (1), p.e2004111-e2004111
• Main Authors: Alam, Muhammad S, Gaida, Matthias M, Debnath, Subrata, Tagad, Harichandra D, Miller Jenkins, Lisa M, Appella, Ettore, Rahman, M Jubayer, Ashwell, Jonathan D
• Format: Article
• Language: English
• Subjects: Activator protein 1; Animals; Antigen receptors, T cell; Antigens; Biology; Biology and Life Sciences; c-Fos protein; Calcineurin; Cancer; Cell activation; Cell Communication; CRISPR; Cytokines; Data collection; Dephosphorylation; Gene expression; Genetic aspects; Genomes; Humans; Immunity, Cellular - genetics; Immunity, Cellular - physiology; Immunology; Kinases; Laboratories; Ligands; Lymphocytes; Lymphocytes T; MAP Kinase Signaling System - physiology; Medical research; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Molecular modelling; NF-AT protein; NF-AT1 protein; NFATC Transcription Factors - metabolism; NFATC Transcription Factors - physiology; Nuclei; p38 Mitogen-Activated Protein Kinases - metabolism; p38 Mitogen-Activated Protein Kinases - physiology; Phosphorylation; Physiological aspects; Properties; Proteins; Proteolysis; Proto-Oncogene Proteins c-fos; Receptors; Receptors, Antigen, T-Cell - physiology; Research and Analysis Methods; Rodents; Substrate Specificity; Substrates; T cell receptors; T cells; T-cell receptor; T-Lymphocytes; Transcription Factors; Tumor necrosis factor-TNF
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.2004111

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. These results demonstrate that the acquisition of unique specificities by TCR-activated p38 orchestrates NFAT-dependent T-cell functions.