Transcriptional regulation of memory B cell differentiation (Homo sapiens)

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Description

Model for signaling pathways and transcription factors that regulate B cell commitment to the germinal center (GC) fate. Boxes that indicate signaling molecules are colored yellow, transcription regulators red, downstream gene targets turquoise and epigenetic modifiers purple. The B cell receptor (BCR), via its signaling subunits Igα and Igβ as well as downstream tyrosine kinases such as SYK and LYN, activates the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT pathways. MAPK signaling induces the expression of the transcriptional activator myocyte enhancer binding factor 2c (MEF2C), which promotes the transcription of B cell lymphoma-extra large (Bcl2l1) and cyclin D2 (Ccnd2). The expression of the transcriptional repressor inhibitor of DNA binding 3 (ID3) is reduced following B cell activation, allowing for transcription factor 3/4 (TCF3/4)-driven induction of Icosl and Mef2b transcription. PI3K/AKT and nuclear factor-κB (NF-κB) signaling also induce the expression of the transcription factor interferon regulatory factor 4 (IRF4). IRF4 and TCF3/4 induce the expression of the co-activator OBF1 (also known as POU class 2 homeobox associating factor 1 (POU2AF1)), which cooperates with OCT2 (also known as POU class 2 homeobox 2 (POU2F2)) to promote transcription of Slamf1, Syk and Il6. OBF1 and OCT2 can also induce the expression of the transcription factor SPI-B, which acts in a redundant fashion with PU.1 to enhance the transcription of genes encoding B cell surface receptors, such as Cd40, B cell activating factor receptor (Baffr), Toll-like receptor 4 (Tlr4) and Tlr9, and many components of the BCR signaling pathway, including Blnk and Btk. Although transiently elevated levels of IRF4 can induce the expression of B cell lymphoma 6 (BCL-6), sustained IRF4 levels will repress BCL-6 expression. BCL-6 expression is also induced by the transcription factors MEF2B and IRF8/PU.1 as well as the cytokines IL-4 and IL-21, which bind to their respective receptors (IL-4R and IL-21R) and induce signal transducer and activator of transcription 6 (STAT6)/STAT3 signaling. CD40 and/or TLR-driven NF-κB signaling, alongside PI3K/AKT signaling, will induce the expression of the transcription factor MYC, which promotes cellular proliferation by inducing the transcription of Ccnd2/Ccnd3 and the expression of the transcription factor E2F transcription factor 1 (E2F1). E2F1 induces expression of Ezh2 that encodes a Polycomb repressive complex 2 (PRC2) enzymatic component. Enhancer of zeste homologue 2 (EZH2) promotes cell cycle progression by repressing the expression of Cdkn1a, Cdkn2a and Cdkn1b, which encode cyclin-dependent kinase inhibitors. EZH2 also promotes E2F1 release from the retinoblastoma (Rb) protein via phosphorylation of Rb, thereby enhancing E2F1 activation and further EZH2 expression. BCL-6 can directly repress MYC expression, thereby limiting the number of cell divisions that GC B cells undergo. BCL-6 promotes GC B cell development through regulation of numerous genes controlling cellular processes including the DNA damage response, B cell migration, apoptosis, BCR and CD40 signaling, plasma cell differentiation and T cell:B cell interactions. Together, these transcriptional regulators allow for the precise control of GC initiation that is necessary to balance the competing needs of the immune system to induce a protective response while limiting immunopathology. Derived from https://pfocr.wikipathways.org/figures/PMC7538181__41577_2020_446_Fig1_HTML.html

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Bibliography

  1. Laidlaw BJ, Cyster JG; ''''; , PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
135858view22:18, 19 November 2024EweitzFix gene symbol, expand gene family
135757view12:03, 9 November 2024EgonwMoved the question mark identifier to a comment
135648view15:32, 14 October 2024EweitzOntology Term : 'B cell' added !
135647view15:30, 14 October 2024EweitzFormally link B cell receptor signaling pathway
135606view18:05, 6 October 2024EweitzConvert "Arrow" to "mim-stimulation"
135605view18:01, 6 October 2024EweitzConvert "Arrow" to "mim-stimulation"
135604view17:51, 6 October 2024EweitzRefine label placement
135603view17:48, 6 October 2024EweitzAdd "Germinal center development"
135602view17:44, 6 October 2024EweitzRefine BCR and CD placement, label "Epigenetic modifier", refine reference
135601view16:36, 6 October 2024EweitzModified description
135600view04:08, 6 October 2024EweitzOntology Term : 'CL:0000236' removed !
135599view04:07, 6 October 2024EweitzOntology Term : 'memory B cell' added !
135598view04:04, 6 October 2024EweitzOntology Term : 'B cell' added !
135597view04:00, 6 October 2024EweitzComplete reference
135596view03:59, 6 October 2024EweitzAdd literature reference
135595view03:55, 6 October 2024EweitzConnect nodes
135594view02:38, 6 October 2024EweitzArrange nodes
135593view01:08, 6 October 2024EweitzAdd more genes
135592view19:00, 5 October 2024EweitzCreate more genes
135591view17:30, 5 October 2024EweitzNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
B cell receptor signalingPathwayWP23 (WikiPathways)
BCL2L1GeneProductENSG00000171552 (Ensembl)
BCL6GeneProductENSG00000113916 (Ensembl)
BCRGeneProductENSG00000186716 (Ensembl)
CCDN2GeneProductENSG00000118971 (Ensembl)
CCND2GeneProductENSG00000118971 (Ensembl)
CCND3GeneProductENSG00000112576 (Ensembl)
CD40GeneProductENSG00000101017 (Ensembl)
CD79AGeneProductENSG00000105369 (Ensembl) Igα (IGa, IGA) in source diagram
CD79BGeneProductENSG00000007312 (Ensembl)
CDKN1AGeneProductENSG00000124762 (Ensembl)
CDKN1BGeneProductENSG00000111276 (Ensembl)
CDKN2AGeneProductENSG00000147889 (Ensembl)
E2F1GeneProductENSG00000101412 (Ensembl)
EZH2GeneProductENSG00000106462 (Ensembl)
Germinal center developmentPathway
ICOSLGGeneProductENSG00000160223 (Ensembl)
ID3GeneProductENSG00000117318 (Ensembl)
IL21RGeneProductENSG00000103522 (Ensembl)
IL4RGeneProductENSG00000077238 (Ensembl)
IL6GeneProductENSG00000136244 (Ensembl)
IRF4GeneProductENSG00000137265 (Ensembl)
IRF8GeneProductENSG00000140968 (Ensembl)
LINGeneProductENSG00000186716 (Ensembl)
MAPK signalingPathwayWP382 (WikiPathways)
MEF2BGeneProductENSG00000213999 (Ensembl)
MEF2CGeneProductENSG00000081189 (Ensembl)
MYCGeneProductENSG00000136997 (Ensembl)
NF-KBPathway
NFKB1GeneProductENSG00000109320 (Ensembl)
PI3K/AKTPathway
POU2AF1GeneProductENSG00000110777 (Ensembl) OBF1 in source diagram
POU2F2GeneProductENSG00000028277 (Ensembl) OCT2 in source diagram
SLAMF1GeneProductENSG00000117090 (Ensembl)
SPI1GeneProductENSG00000066336 (Ensembl) PU.1 in source comment
SPIBGeneProductENSG00000269404 (Ensembl)
STAT3GeneProductENSG00000168610 (Ensembl)
STAT6GeneProductENSG00000166888 (Ensembl)
SYKGeneProductENSG00000165025 (Ensembl)
TCF3GeneProductENSG00000071564 (Ensembl)
TCF4GeneProductENSG00000196628 (Ensembl)
TLR4GeneProductENSG00000136869 (Ensembl)
TLR9GeneProductENSG00000239732 (Ensembl)
TLRGeneProduct? (Ensembl)
TNFRSF13CGeneProductENSG00000159958 (Ensembl) BAFFR in source diagram

Annotated Interactions

No annotated interactions

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