P41183 (BCL6_MOUSE) Reviewed, UniProtKB/Swiss-Prot
Last modified April 16, 2014. Version 124. History...
Names and origin
|Protein names||Recommended name:|
B-cell lymphoma 6 protein homolog
|Organism||Mus musculus (Mouse) [Reference proteome]|
|Taxonomic identifier||10090 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus|
|Sequence length||707 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
Transcriptional repressor mainly required for germinal center (GC) formation and antibody affinity maturation which has different mechanisms of action specific to the lineage and biological functions. Forms complexes with different corepressors and histone deacetylases to repress the transcriptional expression of different subsets of target genes. Represses its target genes by binding directly to the DNA sequence 5'-TTCCTAGAA-3' (BCL6-binding site) or indirectly by repressing the transcriptional activity of transcription factors. In GC B-cells, represses genes that function in differentiation, inflammation, apoptosis and cell cycle control, also autoregulates its transcriptional expression and up-regulates, indirectly, the expression of some genes important for GC reactions, such as AICDA, through the repression of microRNAs expression, like miR155. An important function is to allow GC B-cells to proliferate very rapidly in response to T-cell dependent antigens and tolerate the physiological DNA breaks required for immunglobulin class switch recombination and somatic hypermutation without inducing a p53/TP53-dependent apoptotic response. In follicular helper CD4+ T-cells (T(FH) cells), promotes the expression of T(FH)-related genes but inhibits the differentiation of T(H)1, T(H)2 and T(H)17 cells. Also required for the establishment and maintenance of immunological memory for both T- and B-cells. Suppresses macrophage proliferation through competition with STAT5 for STAT-binding motifs binding on certain target genes, such as CCL2 and CCND2. In response to genotoxic stress, controls cell cycle arrest in GC B-cells in both p53/TP53-dependedent and -independent manners. Besides, also controls neurogenesis through the alteration of the composition of NOTCH-dependent transcriptional complexes at selective NOTCH targets, such as HES5, including the recruitment of the deacetylase SIRT1 and resulting in an epigenetic silencing leading to neuronal differentiation. Ref.6 Ref.7 Ref.9 Ref.10 Ref.12
Homodimer. Interacts (via BTB domain) with the corepressors BCOR, NCOR1 and SMRT/NCOR2; the interactions are direct. Forms preferably ternary complexes with BCOR and SMRT/NCOR2 on target gene promoters but, on enhancer elements, interacts with SMRT/NCOR2 and HDAC3 to repress proximal gene expression. Interacts with histone deacetylases HDAC2, HDAC5 and HDAC9 (via the catalytic domain). Interacts with ZBTB7 and BCL6B. Interacts with SCF(FBXO11) complex; the interaction is independent of phosphorylation and promotes ubiquitination. Interacts (when phosphorylated) with PIN1; the interaction is required for BCL6 degradation upon genotoxic stress. Interacts with ZBTB17; inhibits ZBTB17 transcriptional activity. Interacts with CTBP1, autoinhibits its transcriptional expression. Interacts with NOTCH1 NCID and SIRT1; leads to a epigenetic repression of selective NOTCH1-target genes. Interacts (nor via BTB domain neither acetylated) with the NuRD complex components CHD4, HDAC1, MBD3 and MTA3; the interaction with MTA3 inhibits BCL6 acetylation and is required for BCL6 transpriptional repression. Ref.4 Ref.5 Ref.10 Ref.12
Detected in the cerebral cortex from 12.5 dpc until birth, with highest levels in the frontal and parietal parts of the neocortex than the occipital parts. Ref.10
Interaction with corepressors through the BTB domain is needed to facilitate the rapid proliferation and survival of GC B-cells but is not involved in the T(FH) formation and BCL6-mediated suppression of T(H)2 and T(H)17 differentiation required for GC formation (Ref.12). Ref.12
Phosphorylated by MAPK1 in response to antigen receptor activation at Ser-334 and Ser-344. Phosphorylated by ATM in response to genotoxic stress. Phosphorylation induces its degradation by ubiquitin/proteasome pathway By similarity.
Polyubiquitinated. Polyubiquitinated by SCF(FBXO11), leading to its degradation by the proteasome By similarity.
Acetylated at Lys-380 by EP300 which inhibits the interaction with NuRD complex and the transcriptional repressor function. Deacetylated by HDAC- and SIR2-dependent pathways By similarity.
More than 50% of lethality by 6 weeks of age. Mice have infiltrates of inflammatory cells in their lungs, as well as multinodular lesions with eosinophil infiltrations into the spleen, significantly more T(H)2 and T(H)17 cells and up-regulated levels of inflammtaroy chemokines in macrophages, but, express low levels of memory CD8+ T-cells and, in spleen, GC B and T(FH) cells are both undetectable. B-cells express 10-fold lower levels of surface IgM than control littermates and macrophages divide faster. From 12.5 dpc to at least 21 days after birth, animals have reduced size of the cerebral hemispheres and a reduced thickness of the frontal and parietal cortex with all the cortical layers affected. At 12.5 and 15.5 dpc, marked reduction of cell-cyle exit indicating defective transition from neural progenitor Cells to postmitotic neurons. Ref.6 Ref.7 Ref.10 Ref.12
Contains 1 BTB (POZ) domain.
Contains 6 C2H2-type zinc fingers.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 707||707||B-cell lymphoma 6 protein homolog||PRO_0000047099|
|Domain||32 – 99||68||BTB|
|Zinc finger||519 – 542||24||C2H2-type 1|
|Zinc finger||547 – 569||23||C2H2-type 2|
|Zinc finger||575 – 597||23||C2H2-type 3|
|Zinc finger||603 – 625||23||C2H2-type 4|
|Zinc finger||631 – 653||23||C2H2-type 5|
|Zinc finger||659 – 682||24||C2H2-type 6|
|Region||377 – 380||4||Required for interation with NuRD complex and for transcriptional repressor activity|
Amino acid modifications
|Modified residue||334||1||Phosphoserine; by MAPK1 By similarity|
|Modified residue||344||1||Phosphoserine; by MAPK1 By similarity|
|Modified residue||380||1||N6-acetyllysine; by EP300 By similarity|
|Mutagenesis||21||1||N → K: Abolishes interaction with NCOR2; mice have impaired GC formation and immunoglobulin affinity maturation with lower proliferation and survival of GC B-cells but normal differentiation of helper T-cell subsets and inflammatory response; in macrophages, no effect on transcriptional repression of genes encoding inflammatory molecules; when associated with A-116. In macrophages, no effect on competition with STAT5 for DNA-binding and transcriptional repression of genes encoding inflammatory molecules; when associated with A-116 and 377-Q--Q-380. Ref.11 Ref.12|
|Mutagenesis||116||1||H → A: Abolishes interaction with NCOR2; mice have impaired GC formation and immunoglobulin affinity maturation with lower proliferation and survival of GC B-cells but normal differentiation of helper T-cell subsets and inflammatory response; in macrophages, no effect on transcriptional repression of genes encoding inflammatory molecules; when associated with K-21. In macrophages, no effect on competition with STAT5 for DNA-binding and transcriptional repression of genes encoding inflammatory molecules; when associated with K-21 and 377-Q--Q-380. Ref.11 Ref.12|
|Mutagenesis||377 – 380||4||KKYK → QQYQ in macrophages, no effect on transcriptional repression of genes encoding inflammatory molecules. In macrophages, no effect on competition with STAT5 for DNA-binding and transcriptional repression of genes encoding inflammatory molecules; when associated with K-21 and A-116. Ref.12|
|Mutagenesis||577 – 580||4||CNIC → GNIG in macrophages, inhibits competition with STAT5 for DNA-binding and abolishes transcriptional repression of genes encoding inflammatory molecules. Ref.12|
|Sequence conflict||456||1||A → G in AAB17432. Ref.2|
|||"The murine BCL6 gene is induced in activated lymphocytes as an immediate early gene."|
Fukuda T., Miki T., Yoshida T., Hatano M., Ohashi K., Hirosawa S., Tokuhisa T.
Oncogene 11:1657-1663(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Skeletal muscle.
|||"BCL-6 expression during B-cell activation."|
Allman D., Jain A., Dent A., Maile R.R., Selvaggi T., Kehry M.R., Staudt L.M.
Blood 87:5257-5268(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
|||"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."|
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Olfactory epithelium.
|||"BAZF, a novel Bcl6 homolog, functions as a transcriptional repressor."|
Okabe S., Fukuda T., Ishibashi K., Kojima S., Okada S., Hatano M., Ebara M., Saisho H., Tokuhisa T.
Mol. Cell. Biol. 18:4235-4244(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH BCL6B.
|||"Novel BTB/POZ domain zinc-finger protein, LRF, is a potential target of the LAZ-3/BCL-6 oncogene."|
Davies J.M., Hawe N., Kabarowski J., Huang Q.-H., Zhu J., Brand N.J., Leprince D., Dhordain P., Cook M., Moriss-Kay G., Zelent A.
Oncogene 18:365-375(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH ZBTB7, SUBCELLULAR LOCATION.
|||"BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control."|
Shaffer A.L., Yu X., He Y., Boldrick J., Chan E.P., Staudt L.M.
Immunity 13:199-212(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION AS TRANSCRIPTIONAL REPRESSOR, DISRUPTION PHENOTYPE.
|||"Role for Bcl-6 in the generation and maintenance of memory CD8+ T-cells."|
Ichii H., Sakamoto A., Hatano M., Okada S., Toyama H., Taki S., Arima M., Kuroda Y., Tokuhisa T.
Nat. Immunol. 3:558-563(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN MEMORY CD8(+) T-CELL MAINTENANCE, DISRUPTION PHENOTYPE.
|||"Genotoxic stress regulates expression of the proto-oncogene Bcl6 in germinal center B cells."|
Phan R.T., Saito M., Kitagawa Y., Means A.R., Dalla-Favera R.
Nat. Immunol. 8:1132-1139(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: TISSUE SPECIFICITY.
|||"BCL6 positively regulates AID and germinal center gene expression via repression of miR-155."|
Basso K., Schneider C., Shen Q., Holmes A.B., Setty M., Leslie C., Dalla-Favera R.
J. Exp. Med. 209:2455-2465(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN MIRNA REGULATION, TISSUE SPECIFICITY.
|||"BCL6 controls neurogenesis through Sirt1-dependent epigenetic repression of selective Notch targets."|
Tiberi L., van den Ameele J., Dimidschstein J., Piccirilli J., Gall D., Herpoel A., Bilheu A., Bonnefont J., Iacovino M., Kyba M., Bouschet T., Vanderhaeghen P.
Nat. Neurosci. 15:1627-1635(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN NEUROGENESIS, INTERACTION WITH NOTCH1 AND SIRT1, DEVELOPMENTAL STAGE, DISRUPTION PHENOTYPE.
|||"A hybrid mechanism of action for BCL6 in B cells defined by formation of functionally distinct complexes at enhancers and promoters."|
Hatzi K., Jiang Y., Huang C., Garrett-Bakelman F., Gearhart M.D., Giannopoulou E.G., Zumbo P., Kirouac K., Bhaskara S., Polo J.M., Kormaksson M., Mackerell A.D. Jr., Xue F., Mason C.E., Hiebert S.W., Prive G.G., Cerchietti L., Bardwell V.J., Elemento O., Melnick A.
Cell Rep. 4:578-588(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: MUTAGENESIS OF ASN-21 AND HIS-116.
|||"Lineage-specific functions of Bcl-6 in immunity and inflammation are mediated by distinct biochemical mechanisms."|
Huang C., Hatzi K., Melnick A.
Nat. Immunol. 14:380-388(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN GERMINAL CENTER REACTIONS, DNA-BINDING, DOMAIN, INTERACTION WITH SMRT, DISRUPTION PHENOTYPE, MUTAGENESIS OF ASN-21; HIS-116; 377-LYS--LYS-380 AND 577-CYS--CYS-580.
|+||Additional computationally mapped references.|
|D38377 mRNA. Translation: BAA07456.1.|
U41465 mRNA. Translation: AAB17432.1.
BC052315 mRNA. Translation: AAH52315.1.
|RefSeq||NP_033874.1. NM_009744.3. |
3D structure databases
|SMR||P41183. Positions 5-129, 385-682. |
Protein-protein interaction databases
|BioGrid||198327. 4 interactions.|
|IntAct||P41183. 1 interaction.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSMUST00000023151; ENSMUSP00000023151; ENSMUSG00000022508. |
|UCSC||uc007ytz.1. mouse. |
|MGI||MGI:107187. Bcl6. |
Gene expression databases
Family and domain databases
|Gene3D||220.127.116.11. 5 hits. |
3.30.710.10. 1 hit.
|InterPro||IPR000210. BTB/POZ-like. |
|Pfam||PF00651. BTB. 1 hit. |
|SMART||SM00225. BTB. 1 hit. |
SM00355. ZnF_C2H2. 6 hits.
|SUPFAM||SSF54695. SSF54695. 1 hit. |
|PROSITE||PS50097. BTB. 1 hit. |
PS00028. ZINC_FINGER_C2H2_1. 6 hits.
PS50157. ZINC_FINGER_C2H2_2. 6 hits.
|ChiTaRS||BCL6. mouse. |
|Accession||Primary (citable) accession number: P41183|
Secondary accession number(s): Q61065
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|