Heme regulates B-cell differentiation, antibody class switch, and heme oxygenase-1 expression in B cells as a ligand of Bach2

Watanabe-Matsui, Miki; Muto, Akihiko; Matsui, Toshitaka; Itoh-Nakadai, Ari; Nakajima, Osamu; Murayama, Kazutaka; Yamamoto, Masayuki; Ikeda‐Saito, Masao; Igarashi, Kazuhiko

doi:10.1182/blood-2010-07-296483

Cited by 90 publications

(105 citation statements)

References 47 publications

(87 reference statements)

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“…HO-1 is another common downstream Bach2 gene in T and B cells (Fig.6) (41). Its role in T-and B-cell function is not well known, but we reported that heme, a substrate of HO-1, induces Bach2 degradation and plasma-cell differentiation, suggesting that HO-1 may have a role in this process (41). Collectively, these results suggest that Bach2 regulates a common gene network to maintain the "naive-ness" of T and B cells.…”

Section: Discussionmentioning

confidence: 58%

Bach2 maintains T cells in a naive state by suppressing effector memory-related genes

Tsukumo

Unno

Muto

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The transcriptional repressor BTB and CNC homology 2 (Bach2) is thought to be mainly expressed in B cells with specific functions such as class switch recombination and somatic hypermutation, but its function in T cells is not known. We found equal Bach2 expression in T cells and analyzed its function using Bach2-deficient (−/−) mice. Although T-cell development was normal, numbers of peripheral naive T cells were decreased, which rapidly produced Th2 cytokines after TCR stimulation. Bach2 −/− naive T cells highly expressed genes related to effector-memory T cells such as CCR4, ST-2 and Blimp-1. Enhanced expression of these genes induced Bach2 −/− naive T cells to migrate toward CCR4-ligand and respond to IL33. Forced expression of Bach2 restored the expression of these genes. Using Chromatin Immunoprecipitation (ChIP)-seq analysis, we identified S100 calcium binding protein a, Heme oxigenase 1, and prolyl hydroxylase 3 as Bach2 direct target genes, which are highly expressed in effector-memory T cells. These findings indicate that Bach2 suppresses effector memory-related genes to maintain the naive T-cell state and regulates generation of effector-memory T cells. Kruppel-like factor 2 (KLF2) is one of those TF, which regulates the expression of the sphingosine-1-phosphate receptor-1 (S1pr1) in SP cells (2). S1pr1 is required for the egress of SP cells from the thymus, and thus KLF2-deficient (−/−) SP cells accumulate in the thymus. KLF2 positively regulates S1pr1 expression through direct binding to its promoter. KLF2 −/− mice also develop an unusual population of innate-like CD8 +

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Section: Discussionmentioning

confidence: 58%

Bach2 maintains T cells in a naive state by suppressing effector memory-related genes

Tsukumo

Unno

Muto

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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132

160

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“…In our model using highly purified cell fractions, we found that IL-2-induced ERK signal acts on the PC differentiation associated with an early downregulation of IRF8 and BACH2 expression without any direct effect on PRDM1 at this time point. BACH2 is a PRDM1 inhibitor (51), its inhibition enhances BLIMP1 protein expression (52), and in BCR/ABL-positive cells, BACH2 expression was shown to be repressed via the MEK-ERK pathway (53). In contrast, IRF8 modulates the GC reaction by inducing the expression of BCL6 and AICDA in centroblasts (54).…”

Section: Discussionmentioning

confidence: 99%

IL-2 Requirement for Human Plasma Cell Generation: Coupling Differentiation and Proliferation by Enhancing MAPK–ERK Signaling

Gallou

Caron

Delaloy

et al. 2012

The Journal of Immunology

105

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Mature B cell differentiation involves a well-established transcription factor cascade. However, the temporal dynamics of cell signaling pathways regulating transcription factor network and coordinating cell proliferation and differentiation remain poorly defined. To gain insight into the molecular processes and extrinsic cues required for B cell differentiation, we set up a controlled primary culture system to differentiate human naive B cells into plasma cells (PCs). We identified T cell-produced IL-2 to be critically involved in ERK1/2-triggered PC differentiation. IL-2 drove activated B cell differentiation toward PC independently of its proliferation and survival functions. Indeed, IL-2 potentiated ERK activation and subsequent BACH2 and IRF8 downregulation, sustaining BLIMP1 expression, the master regulator for PC differentiation. Inhibition of the MAPK–ERK pathway, unlike STAT5 signaling, impaired IL-2–induced PC differentiation and rescued the expression profile of BACH2 and IRF8. These results identify IL-2 as a crucial early input in mature B cell fate commitment.

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“…The signal of heme may be transduced as phosphorylation of Bach2. Because heme binding de-stabilizes Bach2 in cells (46), phosphorylation of these residues may be involved in the regulation of protein degradation. Another important point is the fact that many of these phosphorylation sites are within the intrinsically disordered region of Bach2 (35).…”

Section: Discussionmentioning

confidence: 99%

“…To further verify the importance of Ser-535 phosphorylation, we examined the expression of heme oxygenase-1 (HO-1), another established target gene of Bach2 (46). In this experiment, we infected Irf4 Ϫ/Ϫ Irf8 Ϫ/Ϫ pre-B cells with retroviruses expressing either wild type Bach2 or S535A.…”

Section: Mutations Of Bach2 Ser-509 or Ser-535 Reduce The Mobilitymentioning

confidence: 99%

The Transcription Factor Bach2 Is Phosphorylated at Multiple Sites in Murine B Cells but a Single Site Prevents Its Nuclear Localization

Ando¹,

Shima

Tamahara

et al. 2016

Journal of Biological Chemistry

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2), and Irf (3) families have been well studied in the context of the immune system in part due to their clear and established association with the upstream signaling cascades. In contrast, although the phosphatidylinositol 3-kinase (PI3K) pathway is critically important for the regulation of immune cells, its downstream transcription factors are still unclear except for the Foxo family (4). In this study, we investigated the possibility that the transcription factor Bach2 might be regulated in B cells by the PI3K pathway. Salient features of Bach2 relevant to this study are as follows.Bach2 regulates the immune cells at multiple points. During the development of B cells from the progenitor cells, Bach2, together with its related factor Bach1, represses the expression of myeloid genes. The repression of the myeloid program is critical for the progenitor cells to be committed to the B cell fate (5). At the stage of pre-B cells, the successful completion of antibody heavy chain gene rearrangement is monitored by the lack or presence of pre-B cell receptor (pre-BCR 2 checkpoint). Bach2 plays a critical role in negative selection (i.e. elimination of cells unsuccessful in the rearrangement) at the pre-BCR checkpoint (6). In mature B cells, Bach2 is required for the class switch recombination (CSR) and somatic hypermutation that diversify the effector function and antigen affinity, respectively, of antibody molecules in response to antigen and other stimulation (7). Bach2 promotes CSR by delaying the expression of Blimp-1, the master regulator of plasma cell differentiation, and thereby securing a time window for CSR before the terminal differentiation to plasma cells (8 -10). A reduction in the Bach2 expression in memory B cells is involved in their rapid plasma cell differentiation upon antigen re-exposure (11). An integral view of the Bach2 functions in B cells has been proposed as a gene regulatory network (GRN) consisting of Bach2 and other * This work was supported by Grants-in-aid 15H02506, 25670156, 24390066, 23116003, 21249014, 17054028, and 25291042

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Heme regulates B-cell differentiation, antibody class switch, and heme oxygenase-1 expression in B cells as a ligand of Bach2

Cited by 90 publications

References 47 publications

Bach2 maintains T cells in a naive state by suppressing effector memory-related genes

Bach2 maintains T cells in a naive state by suppressing effector memory-related genes

IL-2 Requirement for Human Plasma Cell Generation: Coupling Differentiation and Proliferation by Enhancing MAPK–ERK Signaling

The Transcription Factor Bach2 Is Phosphorylated at Multiple Sites in Murine B Cells but a Single Site Prevents Its Nuclear Localization

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