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• W2063483217 abstract "In this issue of Immunity, Teng et al., 2008Teng G. Hakimpour P. Landgraf P. Rice A. Tuschl T. Casellas R. Papavasiliou F.N. Immunity. 2008; 28 (this issue): 621-629Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar and Dorsett et al., 2008Dorsett Y. McBride K.M. Jankovic M. Gazumyan A. Thai T.-H. Robbiani D.F. DiVirgilio M. Reina San-Martin B. Heidkamp G. Schwickert T. et al.Immunity. 2008; 28 (this issue): 630-638Abstract Full Text Full Text PDF PubMed Scopus (386) Google Scholar report that activation-induced cytidine deaminase in B cells is repressed by microRNA-155. Relief of repression is associated with defective affinity maturation and increased Myc-Igh translocations. In this issue of Immunity, Teng et al., 2008Teng G. Hakimpour P. Landgraf P. Rice A. Tuschl T. Casellas R. Papavasiliou F.N. Immunity. 2008; 28 (this issue): 621-629Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar and Dorsett et al., 2008Dorsett Y. McBride K.M. Jankovic M. Gazumyan A. Thai T.-H. Robbiani D.F. DiVirgilio M. Reina San-Martin B. Heidkamp G. Schwickert T. et al.Immunity. 2008; 28 (this issue): 630-638Abstract Full Text Full Text PDF PubMed Scopus (386) Google Scholar report that activation-induced cytidine deaminase in B cells is repressed by microRNA-155. Relief of repression is associated with defective affinity maturation and increased Myc-Igh translocations. One of the most stunning recent developments in molecular biology is the discovery of microRNAs (miRNAs) and the realization that these hitherto unappreciated entities play pervasive roles in the regulation of gene expression. The sheer profusion of miRNAs and the multiplicity of their targets suggests a staggering ramification of regulatory interactions; mammalian genomes encode at least several hundred and perhaps several thousand miRNAs, each of which might regulate scores of genes through direct interactions and many more through indirect effects. A pair of papers published in this issue of Immunity now cuts through this web of complexity by asking what happens when a single target gene—encoding activation-induced cytidine deaminase (AID)—is relieved of its regulation by a specific miRNA. Despite their diversity, miRNAs are produced by common mechanisms and exert their effects in similar ways (Bartel, 2004Bartel D.P. Cell. 2004; 116: 281-297Abstract Full Text Full Text PDF PubMed Scopus (29448) Google Scholar). The genes that encode miRNAs are transcribed into primary transcripts (pri-miRNAs), from which pre-miRNAs are excised. These stem-loop structures are further trimmed to duplexes of about 22 basepairs by the ribonuclease Dicer, and one of the two strands of the duplex—the functional miRNA—becomes associated with the RNA-induced silencing complex (RISC). Specific basepairing between the miRNA and the transcript of a target gene then represses expression, either by promoting mRNA degradation or by suppressing translation. The accumulation of a particular miRNA is itself controlled at several points, including production of the the primary transcript and processing of pri- and pre-miRNAs. The microRNA miR-155 has drawn particular attention from those interested in B cell biology (Figure 1). The first hints of its importance predate the discovery of vertebrate miRNAs. Induction of B cell lymphomas by avian leukosis virus (ALV) in chickens was associated with integration of ALV into a locus called Bic; the culprit turned out to be a Bic noncoding exon whose overexpression was driven by an ALV promoter (Tam et al., 2002Tam W. Hughes S.H. Hayward W.S. Besmer P. J. Virol. 2002; 76: 4275-4286Crossref PubMed Scopus (139) Google Scholar). The oncogenic activity of this transcript required a conserved region that was later found to span miR-155. Many B cell lymphomas overexpress Bic or miR-155, and B cell-specific expression of a miR-155 transgene promotes polyclonal B cell proliferation in mice (Costinean et al., 2006Costinean S. Zanesi N. Pekarsky Y. Tili E. Volinia S. Heerema N. Croce C.M. Proc. Natl. Acad. Sci. USA. 2006; 103: 7024-7029Crossref PubMed Scopus (953) Google Scholar). In contrast, inefficient processing of primary Bic transcripts contributes to decreased accumulation of miR-155 in Burkitt lymphoma (Kluiver et al., 2007Kluiver J. van den Berg A. de Jong D. Blokzijl T. Harms G. Bouwman E. Jacobs S. Poppema S. Kroesen B.J. Oncogene. 2007; 26: 3769-3776Crossref PubMed Scopus (126) Google Scholar). B cells, T cells, macrophages, and dendritic cells can all express miR-155. Given its presence in multiple cell types and its potential to repress scores of target transcripts, ablation of miR-155 would be expected to have broad effects on gene expression and immune function. This is indeed the case. Mice lacking miR-155 are viable and undergo normal central-lymphoid development but exhibit substantial reductions in germinal center (GC) B cells with accompanying defects in B and T cell function (Rodriguez et al., 2007Rodriguez A. Vigorito E. Clare S. Warren M.V. Couttet P. Soond D.R. van Dongen S. Grocock R.J. Das P.P. Miska E.A. et al.Science. 2007; 316: 608-611Crossref PubMed Scopus (1595) Google Scholar, Thai et al., 2007Thai T.H. Calado D.P. Casola S. Ansel K.M. Xiao C. Xue Y. Murphy A. Frendewey D. Valenzuela D. Kutok J.L. et al.Science. 2007; 316: 604-608Crossref PubMed Scopus (1263) Google Scholar). The miR-155-deficient mice were shown to have a B cell-intrinsic defect in the generation of high-affinity antibody responses to a T cell-dependent antigen (Vigorito et al., 2007Vigorito E. Perks K.L. Abreu-Goodger C. Bunting S. Xiang Z. Kohlhaas S. Das P.P. Miska E.A. Rodriguez A. Bradley A. et al.Immunity. 2007; 27: 847-859Abstract Full Text Full Text PDF PubMed Scopus (660) Google Scholar). These observations suggested that miR-155 has particular importance for GC B cell development. The specific mechanisms underlying these effects, however, would have been impossible to discern. About 60 putative miR-155 targets were overexpressed in miR-155-deficient B cells treated with LPS and IL4—a regimen that mimics aspects of B cell activation in GCs. Among these was the gene encoding the transcriptional activator PU.1, which was validated as a target for miR-155 (Vigorito et al., 2007Vigorito E. Perks K.L. Abreu-Goodger C. Bunting S. Xiang Z. Kohlhaas S. Das P.P. Miska E.A. Rodriguez A. Bradley A. et al.Immunity. 2007; 27: 847-859Abstract Full Text Full Text PDF PubMed Scopus (660) Google Scholar). But PU.1 was but one of many putative targets; more than a hundred additional genes were affected indirectly. Incidentally, the gene that encodes AID (Aicda) was also found to contain a target site for miR-155, and expression was also increased in miR-155-deficient B cells. Which leads us to the work described in this issue of Immunity. The present papers describe the ablation in vivo of an miRNA target site within a single transcript—in this case, the transcript that encodes AID. AID initiates somatic hypermutation (SHM) in GC B cells and is therefore essential for secondary diversification of the antibody repertoire in mice and humans. AID is also essential for class-switch recombination (CSR), which engrafts variable regions of particular specificity and affinity onto heavy-chain constant regions with diverse effector functions. Both of these functions of AID stem from its ability to catalyze deamination of cytosine to uracil; this leads to DNA cleavage through the consecutive actions of uracil DNA glycosidase and APE endonuclease. Teng and coworkers (Teng et al., 2008Teng G. Hakimpour P. Landgraf P. Rice A. Tuschl T. Casellas R. Papavasiliou F.N. Immunity. 2008; 28 (this issue): 621-629Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar) begin with the observation that miR-155 is induced in primary B cells induced by LPS and IL-4 to initiate CSR. Extending previous work, a stringent algorithm identified miR-155 as the only microRNA with a target site in the 3′ UTR of Aicda. The responsiveness of the Aicda 3′ UTR to repression by miR-155 was validated in a transfection assay. The authors next used a bacterial artificial chromosome (BAC) transgenic system to investigate what happens when Aicda is relieved from regulation by miR-155. Already in hand was a mouse strain that carries a BAC transgene covering the region surrounding the Aicda locus. The transgene (termed AID-GFP) encodes an AID-GFP fusion protein that retains catalytic activity and rescues CSR in AID-deficient B cells. The authors constructed a similar indicator strain carrying a BAC transgene (AID-GFP-Mut) in which the miR-155 seed region was mutated. Mice carrying the AID-GFP-Mut transgene differed from control animals carrying the AID-GFP transgene with respect to induction of AID; moreover, mutation of the miR-155 target site perturbed both CSR and affinity maturation. LPS and IL-4 induced higher amounts of the AID-GFP fusion protein in primary B cells from AID-GFP-Mut mice than in B cells from mice bearing the AID-GFP transgene. Moreover, against an AID-deficient genetic background, the AID-GFP-Mut transgene supported a higher frequency of CSR in primary B cells stimulated with LPS and IL-4 than did the AID-GFP transgene. Thus mutation of the miR-155 target site in the Aicda 3′ UTR proved to be of functional consequence. Upon immunization of transgenic mice with a T cell-dependent antigen, AID-GFP was appropriately expressed in GC B cells, although AID-GFP was more highly expressed in mice bearing the mutant transgene, Moreover, in AID-GFP-Mut mice the AID fusion protein was found in B cells circulating in blood, suggesting that mutation of the miR-155 target site allows persistent expression of AID after transit through GCs. Despite overexpression of AID, the AID-GFP-Mut mice showed no change in the frequency or pattern of somatic hypermutation. This result is in fact consistent with earlier indications that the amount of AID is not limiting for somatic hypermutation. Surprisingly, overexpression of AID in the mutant transgenic mice was associated with impaired affinity maturation. The basis for this result is unclear. Examination of circulating B cells revealed greater clonal heterogeneity in AID-GFP-Mut mice than in AID-GFP animals, as well as an increase in the number of mutated clones lacking specific sequence alterations associated with affinity maturation. As the authors indicate, this observation is most consistent with the possibility that in animals persistently expressing AID, low-affinity cells somehow escape the GC. The data do not exclude the possibility—not exclusive of the first—that some cells mutate away from higher affinity through the continuing action of AID. In either event, the impairment of affinity maturation in the AID-GFP-Mut mice remains mysterious. Dorsett and coworkers (Dorsett et al., 2008Dorsett Y. McBride K.M. Jankovic M. Gazumyan A. Thai T.-H. Robbiani D.F. DiVirgilio M. Reina San-Martin B. Heidkamp G. Schwickert T. et al.Immunity. 2008; 28 (this issue): 630-638Abstract Full Text Full Text PDF PubMed Scopus (386) Google Scholar) constructed a mouse strain in which the seed-match nucleotides of the putative miR-155 target site in Aicda are mutated (Aidca155). The authors bred the resulting animals to AID-deficient mice to obtain Aidca155/− heterozygotes. B cells developed normally, but when mice were treated with LPS and IL-4, AID protein and mRNA accumulated to higher amounts in Aidca155/− mice than in Aidca+/− controls; the half-life of Aicda mRNA was prolonged by 2-fold in Aidca155/− B cells. These observations imply that miR-155 regulates AID expression by promoting the degradation of Aicda mRNA. Consistent with the results of Teng et al., Aidca155/− B cells exhibited a higher frequency of CSR than Aidca+/− B cells and exhibited no substantial increase in somatic hypermutation. The most stunning consequence of the Aidca155 mutation, however, is its association with chromosomal translocations involving the Myc and Igh loci. The result can be appreciated in the context of an earlier study in which AID was shown to be essential for the Myc-Igh translocations that accompany expression of an IL-6 transgene (Ramiro et al., 2004Ramiro A.R. Jankovic M. Eisenreich T. Difilippantonio S. Chen-Kiang S. Muramatsu M. Honjo T. Nussenzweig A. Nussenzweig M.C. Cell. 2004; 118: 431-438Abstract Full Text Full Text PDF PubMed Scopus (385) Google Scholar). In the present study, ex vivo treatment of B cells from Aidca155/− mice with LPS- and IL-4-induced Myc-Igh translocations at a frequency 3–6 times greater than in B cells from Aidca+/− mice. An even greater increase in Myc-Igh translocation frequency (about 15-fold) was seen in B cells deficient in miR-155, suggesting that miR-155 counteracts genomic instability by some means in addition to AID repression. Nonetheless, Aidca155/− and miR-155-deficient mice do not show an increase in the incidence of B cell tumors. Thus, although the available data indicate that miR-155 can act as a suppressor of Myc-Igh translocations, relief of this suppressive mechanism seems insufficient to promote frank malignancy. These observations are provocative in light of the paucity of miR-155 in Burkitt's lymphoma, in which Myc-Igh translocations are typical. The ability of the Aidca155 mutation to promote chromosomal translocation in the absence of increased somatic hypermutation is consistent with the interpretation that factors other than AID might be limiting for somatic hypermutation. Indeed, deamination by AID is not always accompanied by extensive mutagenesis; on the contrary, the introduction of mutations through error-prone repair appears to be restricted to a subset of sites upon which AID acts (Liu et al., 2008Liu M. Duke J.L. Richter D.J. Vinuesa C.G. Goodnow C.C. Kleinstein S.H. Schatz D.G. Nature. 2008; 451: 841-845Crossref PubMed Scopus (463) Google Scholar). Thus mutation is not an obligate consequence of AID activity. The Aidca155/− mouse further suggests that in some settings AID might promote genomic instability in the absence of obvious mutagenesis. The demonstration that miR-155 represses the expression of AID—or indeed that any miRNA represses any other transcript—provokes consideration of how the processing of pri- and pre-miRNAs is regulated and how transcription of pri-miRNAs is controlled. Engagement of surface Ig induces Bic transcripts in B cells, but accumulation of miR-155 is not necessarily correlated with accumulation of its pri-miRNA (Kluiver et al., 2007Kluiver J. van den Berg A. de Jong D. Blokzijl T. Harms G. Bouwman E. Jacobs S. Poppema S. Kroesen B.J. Oncogene. 2007; 26: 3769-3776Crossref PubMed Scopus (126) Google Scholar). Clearly, we have much to learn before we can understand how the abundance of miR-155 is governed. Until then, we are left with the question posed by the Roman satirist Juvenal: “Quis custodiet ipsos custodes?”—“Who watches the watchers?”" @default.
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• W2063483217 date "2008-05-01" @default.
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• W2063483217 title "Along Came a Spider: AID Escapes a MicroRNA Web" @default.
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