Multifunctional role of the transcription factor Blimp-1 in coordinating plasma cell differentiation

Minnich, Martina; Tagoh, Hiromi; Bönelt, Peter; Axelsson, Elin; Fischer, Maria; Cebolla, Beatriz; Tarakhovsky, Alexander; Nutt, Stephen L.; Jaritz, Markus; Busslinger, Meinrad

doi:10.1038/ni.3349

Cited by 259 publications

(377 citation statements)

References 76 publications

(151 reference statements)

Supporting

Mentioning

351

Contrasting

Order By: Relevance

“…The cloned promoter was not completely inactivated by PRDM1 suggesting that additional regulatory factors, such as IRF4, may contribute to silencing. PRDM1 has previously been reported to have activating functions in mouse plasma blast (66). There ELL2 was reported as a PRDM1 activated gene, suggesting that the ELL3-to-ELL2 switch can be attributed to both the repressive and activating functions of PRDM1.…”

Section: Discussionmentioning

confidence: 99%

Selective expression of the transcription elongation factor ELL3 in B cells prior to ELL2 drives proliferation and survival

Alexander

Watters

Reusch

et al. 2017

Molecular Immunology

View full text Add to dashboard Cite

B cell activation is dependent on a large increase in transcriptional output followed by focused expression on secreted immunoglobulin as the cell transitions to an antibody producing plasma cell. The rapid transcriptional induction is facilitated by the release of poised RNA pol II into productive elongation through assembly of the super elongation complex (SEC). We report that a SEC component, the Eleven nineteen Lysine-rich leukemia (ELL) family member 3 (ELL3) is dynamically up-regulated in mature and activated human B cells followed by suppression as B cells transition to plasma cells in part mediated by the transcription repressor PRDM1. Burkitt’s lymphoma and a sub-set of Diffuse Large B cell lymphoma cell lines abundantly express ELL3. Depletion of ELL3 in the germinal center derived lymphomas results in severe disruption of DNA replication and cell division along with increased DNA damage and cell death. This restricted utilization and survival dependence reveal a key step in B cell activation and indicate a potential therapeutic target against B cell lymphoma’s with a germinal center origin.

show abstract

Section: Discussionmentioning

confidence: 99%

Selective expression of the transcription elongation factor ELL3 in B cells prior to ELL2 drives proliferation and survival

Alexander

Watters

Reusch

et al. 2017

Molecular Immunology

View full text Add to dashboard Cite

show abstract

“…Further, Rab7 plays an important role in CD40- or TLR-triggered activation of NF-κB, which directly regulates Aicda gene transcription by binding to the promoter and enhancers of this gene (1, 11, 12). Rab7 is, however, dispensable for Erk1/Erk2 activation and expression of Blimp-1, both of which critically mediate plasma cell generation (13, 14), and, as a consequence, B cell differentiation into plasma cells, suggesting that Rab7 and its associated intracellular membrane structures (i.e., endosomes) specify receptor-triggered signaling for selective gene expression and B cell differentiation processes (15). Whether Rab7 plays a role in the maintenance of plasma cells remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Small Molecule Inhibition of Rab7 Impairs B Cell Class Switching and Plasma Cell Survival To Dampen the Autoantibody Response in Murine Lupus

Lam

Kulp

Wang

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

IgG autoantibodies mediate pathology in systemic lupus patients and lupus-prone mice. Here we showed that the class-switched IgG autoantibody response in MRL/Faslpr/lpr and C57/Sle1Sle2Sle2 mice was blocked by the CID 1067700 compound, which specifically targeted Rab7, an endosome-localized small GTPase that was upregulated in activated human and mouse lupus B cells, leading to prevention of disease development and extension of life-span. These were associated with decreased IgG-expressing B cells and plasma cells, but unchanged numbers and functions of myeloid cells and T cells. The Rab7 inhibitor suppressed T cell-dependent and T cell-independent antibody responses, but did not affect T cell-mediated clearance of Chlamydia infection, consistent with a B cell-specific role of Rab7. Indeed, B cells and plasma cells were inherently sensitive to Rab7 gene knockout or Rab7 activity inhibition in class-switching and survival, respectively, while proliferation/survival of B cells and generation of plasma cells were not affected. Impairment of NF-κB activation upon Rab7 inhibition, together with the rescue of B cell class-switching and plasma cell survival by enforced NF-κB activation, indicated that Rab7 mediates these processes by promoting NF-κB activation, likely through signal transduction on intracellular membrane structures. Thus, a single Rab7-inhibiting small molecule can target two stages of B cell differentiation to dampen the pathogenic autoantibody response in lupus.

show abstract

“…Approximately 1-5 ng of cDNA or ChIP-precipitated DNA were used as starting material for the generation of sequencing libraries as described (Minnich et al, 2016). Table S4 provides detailed information about all sequencing experiments of this study.…”

Section: Retroviral Infectionmentioning

confidence: 99%

“…cDNA was prepared from RNA of in vitro-differentiated and ex vivo-sorted cells as previously described (Minnich et al, 2016).…”

Section: Retroviral Infectionmentioning

confidence: 99%

Molecular functions of the transcription factors E2A and E2-2 in controlling germinal center B cell and plasma cell development

Wöhner¹,

Tagoh²,

Bilić³

et al. 2016

J. Cell Biol.

Self Cite

View full text Add to dashboard Cite

1201B cell immunity provides acute and long-term protection of the host against infections through the generation and secretion of high-affinity antibodies that recognize a shear unlimited number of pathogens. This enormous adaptive potential of B cells is brought about by V(D)J recombination of the immunoglobulin heavy chain (Igh) and light chain (Igk and Igl) genes in early B cell development, and by subsequent affinity maturation of the Ig heavy chain in late B cell differentiation (Victora and Nussenzweig, 2012). Somatic hypermutation alters the antigen-binding V H sequences of the Ig heavy-chain, whereas class switch recombination (CSR) exchanges the C H exons to generate Ig isotypes with distinct effector functions (Chaudhuri and Alt, 2004). Whereas the activation-induced deaminase (AID) is an essential regulator of both processes (Muramatsu et al., 2000), somatic hypermutation only takes place in germinal centers (GCs), which are formed upon antigen exposure by the interplay of T follicular helper (Tfh) cells and follicular (FO) B cells in secondary lymphoid organs (Victora and Nussenzweig, 2012). Affinity-based selection in this specialized compartment leads to clonal expansion of B cells expressing high-affinity B cell receptors, which subsequently differentiate to proliferating, antibody-secreting plasmablasts (Victora and Nussenzweig, 2012). Upon migration to specialized bone marrow niches, plasmablasts differentiate into long-lived quiescent plasma cells secreting high amounts of antibodies (Nutt et al., 2015). While many transcription factors are involved in coordinating these B cell responses, we have here studied the role of E-proteins in the regulation of these processes.Basic helix-loop-helix (bHLH) transcription factors can be subdivided into different classes based on biochemical and functional properties (Murre, 2005). Class I bHLH proteins, also known as E-proteins, consist of the three members, E2A (Tcf3), E2-2 (Tcf4), and HEB (Tcf12; Murre, 2005), which bind the E-box (CAN NTG) motif with similar sequence specificity (Fig. S1 A). E-proteins are broadly expressed and heterodimerize with class II bHLH proteins in nonlymphoid cell types. Within the lymphoid system, E-proteins function as homodimers or heterodimers with a different E-protein (Bain et al., 1993;Shen and Kadesch, 1995). E-proteins are thought to mainly function as transcriptional activators, as they interact with the co-activators p300 and CBP (Bradney et al., 2003;Bayly et al., 2004), as well as the promoter recognition factor TFI ID (Chen et al., 2013). The activity of E-proteins is controlled by the inhibitor of DNA binding proteins, which are HLH proteins lacking the basic DNA-binding domain, and are thus capable of sequestering E-proteins into DNA-bindingincompetent heterodimers (Kee, 2009).E-proteins control different aspects of B cell development (Murre, 2005). E2A is required for the commitment of lymphoid progenitors to the B cell lineage (Bain et al.,

show abstract

Multifunctional role of the transcription factor Blimp-1 in coordinating plasma cell differentiation

Cited by 259 publications

References 76 publications

Selective expression of the transcription elongation factor ELL3 in B cells prior to ELL2 drives proliferation and survival

Selective expression of the transcription elongation factor ELL3 in B cells prior to ELL2 drives proliferation and survival

Small Molecule Inhibition of Rab7 Impairs B Cell Class Switching and Plasma Cell Survival To Dampen the Autoantibody Response in Murine Lupus

Molecular functions of the transcription factors E2A and E2-2 in controlling germinal center B cell and plasma cell development

Contact Info

Product

Resources

About