TAPP Adaptors Control B Cell Metabolism by Modulating the Phosphatidylinositol 3-Kinase Signaling Pathway: A Novel Regulatory Circuit Preventing Autoimmunity
| Autor: | Aaron J. Marshall, Affan A. Sher, Kimia Sheikholeslami, Nipun Jayachandran, Edgard M. Mejia, Grant M. Hatch, Sen Hou |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Immunology Autoimmunity Lymphocyte Activation Mice Phosphatidylinositol 3-Kinases 03 medical and health sciences 0302 clinical medicine Phosphatidylinositol Phosphates medicine Animals Immunology and Allergy Phosphorylation Protein kinase B Cells Cultured PI3K/AKT/mTOR pathway B cell B-Lymphocytes Glucose Transporter Type 1 Glycogen Synthase Kinase 3 beta Chemistry Kinase Intracellular Signaling Peptides and Proteins Glucose transporter Membrane Proteins Ribosomal Protein S6 Kinases 70-kDa Germinal center Germinal Center Cell biology Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure Female Phosphatidylinositol 3-kinase signaling Proto-Oncogene Proteins c-akt Signal Transduction 030215 immunology |
| Zdroj: | The Journal of Immunology. 201:406-416 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.1701440 |
| Popis: | Class I PI3K enzymes play critical roles in B cell activation by phosphorylating plasma membrane lipids to generate two distinct phosphoinositide (PI) products, PI(3,4,5)P3 and PI(3,4)P2. These PIs each bind distinct but overlapping sets of intracellular proteins that control cell survival, cytoskeletal reorganization, and metabolic activity. The tandem PH domain containing proteins (TAPPs) bind with high specificity to PI(3,4)P2, and their genetic uncoupling from PI(3,4)P2 in TAPP knock in (KI) mice was previously found to cause chronic B cell activation, abnormal germinal centers (GCs), and autoimmunity. In this article, we find that TAPPs provide feedback regulation affecting PI3K signaling and metabolic activation of B cells. Upon activation, TAPP KI B cells show enhanced metabolic activity associated with increased extracellular acidification rate, increased expression of glucose transporter GLUT1, and increased glucose uptake. TAPP KI B cells show markedly increased activation of the PI3K-regulated kinases Akt, GSK3β, and p70-S6K. Conversely, overexpression of the C-terminal TAPP PH domains in B cells can inhibit Akt phosphorylation by a mechanism requiring the TAPP PI(3,4)P2-binding pocket. Inhibition of the PI3K pathway in TAPP KI B cells reduced GLUT1 expression and glucose uptake, whereas inhibition of Akt alone was not sufficient to normalize these responses. TAPP KI GC B cells also show increased GLUT1 and glucose uptake, and treatment with the inhibitor of glycolysis 2-deoxy-D-glucose reduced chronic GC responses and autoantibody production within these mice. Our findings show that TAPP–PI(3,4)P2 interaction controls activation of glycolysis and highlights the significance of this pathway for B cell activation, GC responses, and autoimmunity. |
| Databáze: | OpenAIRE |
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