The evolutionarily conserved MAPK/Erk signaling promotes ancestral T-cell immunity in fish via c-Myc–mediated glycolysis

• Published in: The Journal of biological chemistry 2020-03, Vol.295 (10), p.3000-3016
• Main Authors: Wei, Xiumei, Zhang, Yu, Li, Cheng, Ai, Kete, Li, Kang, Li, Huiying, Yang, Jialong
• Format: Article
• Language: English
• Subjects: Adaptive Immunity; Aeromonas hydrophila - pathogenicity; ancestral T cells; Animals; cellular immune response; Cichlids - immunology; Cichlids - metabolism; evolution; Evolution, Molecular; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases - classification; Extracellular Signal-Regulated MAP Kinases - metabolism; Fish Diseases - drug therapy; Fish Diseases - immunology; Fish Diseases - microbiology; Fish Proteins - metabolism; Glycolysis; immune regulation; Immunology; Interferon-gamma - metabolism; Lymphocyte Activation; MAP Kinase Signaling System; MAPK/Erk; mitogen-activated protein kinase (MAPK); Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinase Kinases - classification; Mitogen-Activated Protein Kinase Kinases - metabolism; Phosphorylation; Phylogeny; Proto-Oncogene Proteins c-myc - metabolism; Proto-Oncogene Proteins c-raf - metabolism; Pyridones - therapeutic use; Pyrimidinones - therapeutic use; T cell; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; teleost
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.RA119.012231

The mitogen-activated protein kinase (MAPK) cascade is an ancient and evolutionarily conserved signaling pathway involved in numerous physiological processes. Despite great advances in understanding MAPK-mediated regulation of adaptive immune responses in mammals, its contribution to T-cell immunity in early vertebrates remains unclear. Herein, we used Nile tilapia (Oreochromis niloticus) to investigate the regulatory roles of MAPK/extracellular signal–regulated kinase (Erk) signaling in ancestral T-cell immunity of jawed fish. We found that Nile tilapia possesses an evolutionarily conserved MAPK/Erk axis that is activated through a classical three-tier kinase cascade, involving sequential phosphorylation of RAF proto-oncogene serine/threonine-protein kinase (Raf), MAPK/Erk kinase 1/2 (Mek1/2), and Erk1/2. In Nile tilapia, MAPK/Erk signaling participates in adaptive immune responses during bacterial infection. Upon T-cell activation, the MAPK/Erk axis is robustly activated, and MAPK/Erk blockade by specific inhibitors severely impairs T-cell activation. Furthermore, signals from MAPK/Erk were indispensable for primordial T cells to proliferate and exert their effector functions. Mechanistically, activation of the MAPK/Erk axis promoted glycolysis via induction of the transcriptional regulator proto-oncogene c-Myc (c-Myc), to ensure the proper activation and proliferation of fish T cells. Our results reveal the regulatory mechanisms of MAPK/Erk signaling in T-cell immunity in fish and highlight a close link between immune signals and metabolic programs. We propose that regulation of T-cell immunity by MAPK/Erk is a basic and sophisticated strategy that evolved before the emergence of the tetrapod lineage. These findings shed light on the evolution of the adaptive immune system.