MicroRNAs (miRNAs) are small non-coding RNAs of ∼21 nucleotides in length that regulate gene expression at the post-transcriptional level. Recent studies using loss- or gain-of-function approaches have indicated a role for the miRNA miR-155 in regulating the expression of hundreds of mRNAs and in germinal-centre reactions. However, the direct target(s) of miR-155 in B cells is still unclear. Now, two papers published in Immunity identify activation-induced cytidine deaminase (AID), a potent DNA mutator that is required for antibody diversification in B cells, as a direct target for miR-155-mediated suppression.
AID initiates the induction of somatic hypermutation and class-switch recombination (CSR), which together lead to the selection of high-affinity B cells in germinal centres, but because it is a DNA mutator, AID expression must be tightly regulated in the cell. Using several miRNA target-prediction algorithms, Teng et al. confirmed that Aicda , the gene encoding AID, contains a target sequence for miR-155 in its 3′-untranslated region. In addition, miR-155 expression was shown to be upregulated in B cells undergoing CSR induced by lipopolysaccharide (LPS) and interleukin-4 (IL-4).
To determine whether there is a functional interaction between miR-155 and AID, the authors generated transgenic mice expressing an Aicda transgene that contained a mutated miR-155 target site and that was tagged with green fluorescent protein (mutant Aicda mice). Following in vitro stimulation with LPS and IL-4, AID was more rapidly induced and its level of expression was higher in splenic B cells from mutant Aicda mice than in cells from control mice. In addition, increased CSR was observed in B cells from Aicda mutant mice crossed with Aicda−/− mice (to exclude the contribution of endogenous AID) following stimulation. So, the data show that miR-155 directly regulates the quantitative and temporal expression of AID in B cells. These observations were confirmed in vivo and further analysis revealed that the disruption of the interaction between miR-155 and Aicda in mutant mice resulted in impaired affinity maturation of B cells.
Dorsett et al. also generated mice in which the miR-155 target site in Aicda was mutated (Aicda155/+ mice) and these mice were then crossed with Aicda−/− mice to produce Aicda155/− mice. Similar to the results of Teng et al., the amount of AID expressed and the level of CSR was higher in B cells from Aicda155/− mice compared with those from Aicda+/− mice following stimulation with LPS and IL-4.
It is known that AID induces oncogenic chromosomal translocations between Myc and Igh, which are associated with Burkitt's lymphoma. The authors found that the frequency of Myc–Igh translocations was higher in Aicda155/− mice than Aicda+/− mice. In addition, the frequency of translocations was even higher in miR-155-deficient mice, indicating that miR-155 expression suppresses Myc–Igh translocations, at least in part, through the regulation of AID expression.
Taken together, these studies show that miR-155 suppresses the expression of AID in activated B cells and that removal of this suppression results in defective affinity maturation and increased Myc–Igh translocations.
References
ORIGINAL RESEARCH PAPER
Teng, G. et al. MicroRNA-155 is a negative regulator of activation-induced cytidine deaminase. Immunity 28, 621–629 (2008)
Dorsett, Y. et al. MicroRNA-155 suppresses activation-induced cytidine deaminase-mediated Myc-Igh translocation. Immunity 28, 630–638 (2008)
FURTHER READING
Lodish, H. F. et al. Micromanagement of the immune system by microRNAs. Nature Rev. Immunol. 8, 120–130 (2008)
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Leavy, O. (micro)Restraint of AID. Nat Rev Immunol 8, 493 (2008). https://doi.org/10.1038/nri2364
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DOI: https://doi.org/10.1038/nri2364