scholarly journals ERK phosphorylation is RAF independent in naïve and activated B cells but RAF dependent in plasma cell differentiation

2021 ◽  
Vol 14 (682) ◽  
pp. eabc1648
Author(s):  
Laura Scheffler ◽  
Samantha Feicht ◽  
Tea Babushku ◽  
Laura B. Kuhn ◽  
Stefanie Ehrenberg ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
Plasma Cell ◽  
Mitogen Activated Protein Kinase ◽  
Plasma Cell Differentiation ◽  
Erk Phosphorylation ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase ◽  
Activated B Cells

Members of the RAF family of serine-threonine kinases are intermediates in the mitogen-activated protein kinase and extracellular signal–regulated kinase (MAPK-ERK) signaling pathway, which controls key differentiation processes in B cells. By analyzing mice with B cell–specific deletion of Raf1, Braf, or both, we showed that Raf-1 and B-Raf acted together in mediating the positive selection of pre-B and transitional B cells as well as in initiating plasma cell differentiation. However, genetic or chemical inactivation of RAFs led to increased ERK phosphorylation in mature B cells. ERK activation in the absence of Raf-1 and B-Raf was mediated by multiple RAF-independent pathways, with phosphoinositide 3-kinase (PI3K) playing an important role. Furthermore, we found that ERK phosphorylation strongly increased during the transition from activated B cells to pre-plasmablasts. This increase in ERK phosphorylation did not occur in B cells lacking both Raf-1 and B-Raf, which most likely explains the partial block of plasma cell differentiation in mice lacking both RAFs. Collectively, our data indicate that B-Raf and Raf-1 are not necessary to mediate ERK phosphorylation in naïve or activated B cells but are essential for mediating the marked increase in ERK phosphorylation during the transition from activated B cells to pre-plasmablasts.

scholarly journals Transmembrane activator, calcium modulator, and cyclophilin ligand interactor drives plasma cell differentiation in LPS-activated B cells

2009 ◽  
Vol 123 (6) ◽  
pp. 1277-1286.e5 ◽  
Author(s):  
Esra Ozcan ◽  
Lilit Garibyan ◽  
John Jhe-Yun Lee ◽  
Richard J. Bram ◽  
Kong-Peng Lam ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
Plasma Cell ◽  
Plasma Cell Differentiation ◽  
Activated B Cells

TACI Drives Plasma Cell Differentiation in LPS Activated B Cells

2009 ◽  
Vol 123 (2) ◽  
pp. S94-S94
Author(s):  
E. Ozcan ◽  
L. Garibyan ◽  
J.J.Y. Lee ◽  
R.S. Geha
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
Plasma Cell ◽  
Plasma Cell Differentiation ◽  
Activated B Cells

scholarly journals The AP-1 transcription factor Fra1 inhibits follicular B cell differentiation into plasma cells

2014 ◽  
Vol 211 (11) ◽  
pp. 2199-2212 ◽  
Author(s):  
Bettina Grötsch ◽  
Sebastian Brachs ◽  
Christiane Lang ◽  
Julia Luther ◽  
Anja Derer ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Plasma Cell ◽  
Cell Activation ◽  
Plasma Cells ◽  
Regulatory Gene ◽  
B Cell Differentiation ◽  
Plasma Cell Differentiation ◽  
Activated B Cells

The cornerstone of humoral immunity is the differentiation of B cells into antibody-secreting plasma cells. This process is tightly controlled by a regulatory gene network centered on the transcriptional repressor B lymphocyte–induced maturation protein 1 (Blimp1). Proliferation of activated B cells is required to foster Blimp1 expression but needs to be terminated to avoid overshooting immune reactions. Activator protein 1 (AP-1) transcription factors become quickly up-regulated upon B cell activation. We demonstrate that Fra1, a Fos member of AP-1, enhances activation-induced cell death upon induction in activated B cells. Moreover, mice with B cell–specific deletion of Fra1 show enhanced plasma cell differentiation and exacerbated antibody responses. In contrast, transgenic overexpression of Fra1 blocks plasma cell differentiation and immunoglobulin production, which cannot be rescued by Bcl2. On the molecular level, Fra1 represses Blimp1 expression and interferes with binding of the activating AP-1 member c-Fos to the Blimp1 promoter. Conversely, overexpression of c-Fos in Fra1 transgenic B cells releases Blimp1 repression. As Fra1 lacks transcriptional transactivation domains, we propose that Fra1 inhibits Blimp1 expression and negatively controls plasma cell differentiation through binding to the Blimp1 promoter. In summary, we demonstrate that Fra1 negatively controls plasma cell differentiation by repressing Blimp1 expression.

Genomic deletion of the whole IgH 3′ regulatory region (hs3a, hs1,2, hs3b, and hs4) dramatically affects class switch recombination and Ig secretion to all isotypes

Blood ◽  
2010 ◽  
Vol 116 (11) ◽  
pp. 1895-1898 ◽  
Author(s):  
Christelle Vincent-Fabert ◽  
Remi Fiancette ◽  
Eric Pinaud ◽  
Véronique Truffinet ◽  
Nadine Cogné ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
Plasma Cell ◽  
Regulatory Region ◽  
Class Switch Recombination ◽  
B Cell Differentiation ◽  
Plasma Cell Differentiation ◽  
Heavy Chains ◽  
Class Switch ◽  
Transcriptional Changes

Abstract The immunoglobulin heavy chain locus (IgH) undergoes multiple changes along B-cell differentiation. In progenitor B cells, V(D)J assembly allows expression of μ heavy chains. In mature B cells, class switch recombination may replace the expressed constant (C)μ gene with a downstream CH gene. Finally, plasma cell differentiation strongly boosts IgH transcription. How the multiple IgH transcriptional enhancers tune these changes is unclear. Here we demonstrate that deletion of the whole IgH 3′ regulatory region (3′RR) allows normal maturation until the stage of IgM/IgD expressing lymphocytes, but nearly abrogates class switch recombination to all CH genes. Although plasma cell numbers are unaffected, we reveal the role of the 3′RR into the transcriptional burst normally associated with plasma cell differentiation. Our study shows that transcriptional changes and recombinations occurring after antigen-encounter appear mainly controlled by the 3′RR working as a single functional unit.

scholarly journals Down-regulation of BLIMP1α by the EBV oncogene, LMP-1, disrupts the plasma cell differentiation program and prevents viral replication in B cells: implications for the pathogenesis of EBV-associated B-cell lymphomas

Blood ◽  
2011 ◽  
Vol 117 (22) ◽  
pp. 5907-5917 ◽  
Author(s):  
Katerina Vrzalikova ◽  
Martina Vockerodt ◽  
Sarah Leonard ◽  
Andrew Bell ◽  
Wenbin Wei ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Virus Replication ◽  
Plasma Cell ◽  
Germinal Center ◽  
Lytic Cycle ◽  
Transformed Cells ◽  
Down Regulation ◽  
Plasma Cell Differentiation

AbstractAn important pathogenic event in Epstein-Barr virus (EBV)-associated lymphomas is the suppression of virus replication, which would otherwise lead to cell death. Because virus replication in B cells is intimately linked to their differentiation toward plasma cells, we asked whether the physiologic signals that drive normal B-cell differentiation are absent in EBV-transformed cells. We focused on BLIMP1α, a transcription factor that is required for plasma cell differentiation and that is inactivated in diffuse large B-cell lymphomas. We show that BLIMP1α expression is down-regulated after EBV infection of primary germinal center B cells and that the EBV oncogene, latent membrane protein-1 (LMP-1), is alone capable of inducing this down-regulation in these cells. Furthermore, the down-regulation of BLIMP1α by LMP-1 was accompanied by a partial disruption of the BLIMP1α transcriptional program, including the aberrant induction of MYC, the repression of which is required for terminal differentiation. Finally, we show that the ectopic expression of BLIMP1α in EBV-transformed cells can induce the viral lytic cycle. Our results suggest that LMP-1 expression in progenitor germinal center B cells could contribute to the pathogenesis of EBV-associated lymphomas by down-regulating BLIMP1α, in turn preventing plasma cell differentiation and induction of the viral lytic cycle.

scholarly journals TLR9 Signaling Suppresses the Canonical Plasma Cell Differentiation Program in Follicular B Cells

2018 ◽  
Vol 9 ◽  
Author(s):  
Bárbara José Antunes Baptista ◽  
Alessandra Granato ◽  
Fábio B. Canto ◽  
Fabricio Montalvão ◽  
Lucas Tostes ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
Plasma Cell ◽  
Plasma Cell Differentiation ◽  
Follicular B Cells ◽  
Tlr9 Signaling
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