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PRDM1

From Wikipedia, the free encyclopedia
PRDM1
Available structures
PDBOrtholog search:PDBeRCSB
Identifiers
AliasesPRDM1,BLIMP1, PRDI-BF1, PR domain 1, PR/SET domain 1
External IDsOMIM:603423;MGI:99655;HomoloGene:925;GeneCards:PRDM1;OMA:PRDM1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

639

12142

Ensembl

ENSG00000057657

ENSMUSG00000038151

UniProt

O75626

Q60636

RefSeq (mRNA)

NM_001198
NM_182907

NM_007548

RefSeq (protein)

NP_001189
NP_878911

Location (UCSC)Chr 6: 105.99 – 106.11 MbChr 10: 44.31 – 44.4 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

PR domain zinc finger protein 1,or B lymphocyte-induced maturation protein-1 (BLIMP-1), is aproteinin humans encoded by the genePRDM1located on chromosome 6q21.[5]BLIMP-1 is considered a 'master regulator' ofhematopoietic stem cells,and plays a critical role in the development ofplasma B cells,T cells,dendritic cells (DCs),macrophages,andosteoclasts.Pattern Recognition Receptors (PRRs)can activate BLIMP-1, both as a direct target and through downstream activation.[6][7][8]BLIMP-1 is a transcription factor that triggers expression of many downstream signaling cascades.[6][9][10][11]As a fine-tuned and contextual rheostat of the immune system, BLIMP-1 up- or down-regulates immune responses depending on the precise scenarios.[6][10][12]BLIMP-1 is highly expressed inexhausted T-cells– clones of dysfunctional T-cells with diminished functions due to chronic immune response against cancer, viral infections, or organ transplant.[7][8][13][14]

Function

[edit]
The regulatory role of BLIMP-1/PRDM1 on immunocytokines and hematopoietic cells.
PRDM1/BLIMP-1 is a master transcription factor regulating downstream cytokines. It is activated by TLRs and IRF-4, and is crucial in T cell, B cell, and myeloid lineage cell differentiations.

As a potent repressor ofbeta-interferon (IFN-β),BLIMP-1 competes for interferon regulatory factors (IRF) binding sites in the IFN-β promoter due to its sequence similarity withIRF1and IRF2.[6][9]However, BLIMP-1 cools down and activates immune responses in a highly contextual manner. BLIMP-1 repressesNFκB/TNF-Rpathway repressorNLRP12,thus indirectly activating the immune response.[6]BLIMP-1 expression is also upregulated by danger signals from double-stranded RNA (specific to virus),lipopolysaccharides(specific togram-negative bacteria),unmethylated CpG DNA(abundant in bacterial genomes), and cancer inflammation viaToll-like receptor (TLR) 3,TLR-4,TLR-9,andSTATsignaling, respectively.[6][9]

The increased expression of the BLIMP-1 protein inB lymphocytes,T lymphocytes,NK cellsand other immune system cells leads to an immune response through proliferation and differentiation of antibody secretingplasma cells.In a monocytic cell line, over-expression of BLIMP-1 can lead to differentiation into maturemacrophages.BLIMP-1 also plays a role inosteoclastogenesisas well as in the modulation ofdendritic cells.Other cells of the immune system such as human peripheral bloodmonocytesandgranulocytesalso express BLIMP-1.[6][10][11]

As a transcriptionalrepressor,BLIMP-1 has a critical role in the foundation of the mousegerm celllineage, as its disruption causes a block early in the process of primordial germ cell formation. BLIMP-1-deficient mutant embryos form a tight cluster of about 20 primordial germ cell-like cells, which fail to show the characteristic migration, proliferation and consistent repression ofhomeoboxgenes that normally accompany specification of primordial germ cells. BLIMP-1 is widely expressed instem cellsof developing embryos.[6]The genetic lineage-tracing experiments indicate that the BLIMP-1-positive cells originating from the proximal posteriorepiblastcells are indeed the lineage-restricted primordial germ cell precursors.[15]

B cell development

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BLIMP-1 is an important regulator of plasma cell differentiation. During B cell development, a B cell can either differentiate into a short-lived plasma cell or into a germinal center B cell after receiving proper activation and co-stimulation.[6][10]BLIMP-1 acts as a master gene regulating the transcriptional network that regulates B cell terminal differentiation. Except fornaïveandmemory B cells,all antibody secreting cells express BLIMP-1 regardless of their location and differentiation history.[5]BLIMP-1 directly initiatesunfolded protein response (UPR)by activating Ire1,Xbp1,andArf6,allowing theplasma Bcells to produce vast amounts of antibody.[6][12]BLIMP-1 expression is carefully controlled: the expression of BLIMP-1 is low or undetectable in primary B cells, and only upregulated in plasmablasts and plasma cells.[16]BLIMP-1 is a direct transcriptional target of IRF-4, which is also necessary for B-cell differentiation.[6]The premature expression of BLIMP-1 in primary B cells results in cell death, so only cells that are ready to initiate transcription driven by BLIMP-1 are able to survive and differentiate.[5][13]However, without BLIMP-1, proliferating B cells are unable to differentiate to plasma cells, resulting in severe reduction in production of all isotypes ofimmunoglobulin.[5]

T cell development

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BLIMP-1 promotes naive T-cells to differentiate into T-helper (Th) 2 lineage, while repressing the differentiation into Th1, Th17, and follicular Th.[9]BLIMP-1 is also required for differentiation ofcytotoxic T-cell.[13]Specifically, the expression ofgranzyme B(a source of cytotoxicity) in Tc depends on the presence of BLIMP-1 and interleukin-2 (IL-2) cytokine.[6][9]

BLIMP-1 is a gatekeeper of T-cell activation and plays a key role in maintaining normal T cellhomeostasis.BLIMP-1 deficiency leads to high numbers of activated T helper cells and severe autoimmune diseases in laboratory mice.[13]BLIMP-1 is important in dampening autoimmunity, as well as antiviral and antitumor responses.[13]BLIMP-1 regulates T cell activation through a negative feedback loop: T cell activation leads to IL-2 production, IL-2 leads to PRDM1 transcription, and BLIMP-1 feeds back to repress IL-2 gene transcription.[5]

T cell exhaustion

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Multiple studies have reported high expression of BLIMP-1 inexhausted T cells.[13][14]T cell exhaustion is usually a result of chronic immune activations, commonly caused by viral infection (e.g. HIV), cancer, or organ transplant.[7][13][14]High expression of BLIMP-1 in Tc and Th cells is associated with the transcription of receptors inhibiting immune responses, though it is unclear whether the relation between BLIMP-1 expression and T-cell exhaustion is causal or just associative.[8]

BLIMP-1 helps the production of short-lived effector T cells and clonally exhausted T cells. It also helps with the migration of T cells out of the spleen and lymph nodes into peripheral tissues. However, BLIMP-1 does not promote the production of long-lived effector memory cells. BLIMP-1 allows the production of some longer lived effector memory cells but its absence allows for the generation of long term central memory cells, which are thought to have a higher potential of proliferation on secondary challenge.[17]

DCs and macrophages development

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BLIMP-1 has been shown in vitro as a cell lineage determinant inmonocytes,inducing their differentiation intoDCsandmacrophages.It is speculated to have the similar effects in vivo.[6][9]In addition, BLIMP-1 also suppressed myeloid cells from differentiating intogranulocytes,which includes eosinophil, basophil, and neutrophils.[6][9]The role of BLIMP-1 in DCs and macrophages development is a matter of interest because analysis have suggested that DCs, rather than B-cells, is the way in which individual withsingle nucleotide polymorphisms(SNP) near BLIMP-1 (specifically, rs548234 in Han Chinese, and rs6568431 in European) are predisposed toSystemic Lupus Erythematosus(SLE).[6][9]

Osteoclast development

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Osteoclastsare multinucleated cells that break down and resorb bone tissues.[6][18]Together withosteoblasts,which form new bones, osteoclast helps maintain and repair bone in vertebrates.[18]BLIMP-1 directly and indirectly represses anti-osteoclastogenesis genes such asBcl6,IRF8,andMafB,helping monocytes differentiate into osteoclasts.[6]In mice, insufficient expression of BLIMP-1 in osteoclast progenitors would lead to abnormal development of the skeleton.[6]

[edit]

SNPs near the PRDM1 gene have been identified ingenome-wide association studies (GWAS)to be linked tolupus (SLE)andrheumatoid arthritis (RA).[9]BLIMP-1 represses the expression of the proinflammatory cytokineInterleukin-6(IL-6), andcathepsin S(CTSS), which promotes antigen processing and presentation. BLIMP-1 deficiency and IL-6 overexpression were linked toinflammatory bowel disease (IBD)and SLE.[6]

AnotherGWAShas identified two genetic variations near the PRDM1 gene that predict an increased likelihood of developing a second cancer after radiation treatment forHodgkin lymphoma.[19]

References

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  1. ^abcGRCh38: Ensembl release 89: ENSG00000057657–Ensembl,May 2017
  2. ^abcGRCm38: Ensembl release 89: ENSMUSG00000038151–Ensembl,May 2017
  3. ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^abcdeBoi M, Zucca E, Inghirami G, Bertoni F (May 2015). "PRDM1/BLIMP1: a tumor suppressor gene in B and T cell lymphomas".Leukemia & Lymphoma.56(5): 1223–1228.doi:10.3109/10428194.2014.953155.PMID25115512.S2CID7518347.
  6. ^abcdefghijklmnopqrsUlmert I, Henriques-Oliveira L, Pereira CF, Lahl K (December 2020)."Mononuclear phagocyte regulation by the transcription factor Blimp-1 in health and disease".Immunology.161(4): 303–313.doi:10.1111/imm.13249.PMC7692253.PMID32799350.
  7. ^abcWells AD, Li XC, Strom TB, Turka LA (May 2001)."The role of peripheral T-cell deletion in transplantation tolerance".Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences.356(1409): 617–623.doi:10.1098/rstb.2001.0845.PMC1088449.PMID11375065.
  8. ^abcCrawford A, Angelosanto JM, Kao C, Doering TA, Odorizzi PM, Barnett BE, Wherry EJ (February 2014)."Molecular and transcriptional basis of CD4⁺ T cell dysfunction during chronic infection".Immunity.40(2): 289–302.doi:10.1016/j.immuni.2014.01.005.PMC3990591.PMID24530057.
  9. ^abcdefghiKim SJ (December 2015)."Immunological function of Blimp-1 in dendritic cells and relevance to autoimmune diseases".Immunologic Research.63(1–3): 113–120.doi:10.1007/s12026-015-8694-5.PMC4651792.PMID26376898.
  10. ^abcdTurner, C. Alexander; Mack, David H.; Davis, Mark M. (1994-04-22)."Blimp-1, a novel zinc finger-containing protein that can drive the maturation of B lymphocytes into immunoglobulin-secreting cells".Cell.77(2): 297–306.doi:10.1016/0092-8674(94)90321-2.ISSN0092-8674.PMID8168136.S2CID46200658.
  11. ^abSciammas R, Davis MM (May 2004)."Modular nature of Blimp-1 in the regulation of gene expression during B cell maturation".Journal of Immunology.172(9): 5427–5440.doi:10.4049/jimmunol.172.9.5427.PMID15100284.
  12. ^abTellier J, Nutt SL (January 2019)."Plasma cells: The programming of an antibody-secreting machine".European Journal of Immunology.49(1): 30–37.doi:10.1002/eji.201847517.hdl:11343/284565.PMID30273443.S2CID52901472.
  13. ^abcdefgFu SH, Yeh LT, Chu CC, Yen BL,Sytwu HK(July 2017)."New insights into Blimp-1 in T lymphocytes: a divergent regulator of cell destiny and effector function".Journal of Biomedical Science.24(1): 49.doi:10.1186/s12929-017-0354-8.PMC5520377.PMID28732506.
  14. ^abcCollier JL, Weiss SA, Pauken KE, Sen DR, Sharpe AH (July 2021)."Not-so-opposite ends of the spectrum: CD8+T cell dysfunction across chronic infection, cancer and autoimmunity ".Nature Immunology.22(7): 809–819.doi:10.1038/s41590-021-00949-7.PMC9197228.PMID34140679.
  15. ^Ohinata Y, Payer B, O'Carroll D, Ancelin K, Ono Y, Sano M, et al. (July 2005). "Blimp1 is a critical determinant of the germ cell lineage in mice".Nature.436(7048): 207–213.Bibcode:2005Natur.436..207O.doi:10.1038/nature03813.PMID15937476.S2CID4399840.
  16. ^Moroney JB, Chupp DP, Xu Z, Zan H, Casali P (December 2020)."Epigenetics of the antibody and autoantibody response".Current Opinion in Immunology.Autoimmunity.67:75–86.doi:10.1016/j.coi.2020.09.004.PMC7744442.PMID33176228.
  17. ^Welsh RM (August 2009)."Blimp hovers over T cell immunity".Immunity.31(2): 178–180.doi:10.1016/j.immuni.2009.08.005.PMC3220184.PMID19699168.
  18. ^abFlorencio-Silva R, Sasso GR, Sasso-Cerri E, Simões MJ, Cerri PS (2015-07-13)."Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells".BioMed Research International.2015:421746.doi:10.1155/2015/421746.PMC4515490.PMID26247020.
  19. ^Best T, Li D, Skol AD, Kirchhoff T, Jackson SA, Yasui Y, et al. (July 2011)."Variants at 6q21 implicate PRDM1 in the etiology of therapy-induced second malignancies after Hodgkin's lymphoma".Nature Medicine.17(8): 941–943.doi:10.1038/nm.2407.PMC3229923.PMID21785431.

Further reading

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This article incorporates text from theUnited States National Library of Medicine,which is in thepublic domain.

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