The mTORC1/4E-BP/eIF4E Axis Promotes Antibody Class Switching in B Lymphocytes
| Autor: | Chiu, Honyin, Jackson, Leandra V, Oh, Kwon Ik, Mai, Annie, Ronai, Ze'ev A, Ruggero, Davide, Fruman, David A |
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| Rok vydání: | 2019 |
| Předmět: |
Cells
1.1 Normal biological development and functioning Immunology Cell Cycle Proteins Mechanistic Target of Rapamycin Complex 1 Inbred C57BL Transgenic Mice Underpinning research Genetics Animals 2.1 Biological and endogenous factors Eukaryotic Initiation Factors Aetiology Sirolimus B-Lymphocytes Cultured Signal Transducing Adaptor Proteins Phosphoproteins Immunoglobulin Class Switching Eukaryotic Initiation Factor-4E Infectious Diseases Gene Expression Regulation Protein Biosynthesis Generic health relevance Carrier Proteins Signal Transduction Protein Binding |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950), vol 202, iss 2 |
| Popis: | During an adaptive immune response, activated mature B cells give rise to Ab-secreting plasma cells to fight infection. B cells undergo Ab class switching to produce different classes of Abs with varying effector functions. The mammalian/mechanistic target of rapamycin (mTOR) signaling pathway is activated during this process, and disrupting mTOR complex 1 (mTORC1) in B cells impairs class switching by a poorly understood mechanism. In particular, it is unclear which mTORC1 downstream substrates control this process. In this study, we used an in vitro murine model in which the mTORC1 inhibitor rapamycin, when added after a B cell has committed to divide, suppresses class switching while preserving proliferation. Investigation of mTORC1 substrates revealed a role for eukaryotic translation initiation factor 4E (eIF4E) and eIF4E-binding proteins in class switching. Mechanistically, we show that genetic or pharmacological disruption of eIF4E binding to eIF4G reduced cap-dependent translation, which specifically affected the expression of activation-induced cytidine deaminase protein but not Aicda mRNA. This translational impairment decreased Ab class switching independently of proliferation. These results uncover a previously undescribed role for mTORC1 and the eIF4E-binding proteins/eIF4E axis in activation-induced cytidine deaminase protein expression and Ab class switching in mouse B cells, suggesting that cap-dependent translation regulates key steps in B cell differentiation. |
| Databáze: | OpenAIRE |
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