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PRDM1

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PRDM1
Available structures
PDBOrtholog search: PDBe RCSB
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
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

PR domain zinc finger protein 1, or B lymphocyte-induced maturation protein-1 (BLIMP-1), is a protein in humans encoded by the gene PRDM1 located on chromosome 6q21.[5] BLIMP-1 is considered a 'master regulator' of hematopoietic stem cells, and plays a critical role in the development of plasma B cells, T cells, dendritic cells (DCs), macrophages, and osteoclasts. 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 in exhausted 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

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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 of beta-interferon (IFN-β), BLIMP-1 competes for interferon regulatory factors (IRF) binding sites in the IFN-β promoter due to its sequence similarity with IRF1 and IRF2.[6][9] However, BLIMP-1 cools down and activates immune responses in a highly contextual manner. BLIMP-1 represses NFκB/TNF-R pathway repressor NLRP12, 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 to gram-negative bacteria), unmethylated CpG DNA (abundant in bacterial genomes), and cancer inflammation via Toll-like receptor (TLR) 3, TLR-4, TLR-9, and STAT signaling, respectively.[6][9]

The increased expression of the BLIMP-1 protein in B lymphocytes, T lymphocytes, NK cells and other immune system cells leads to an immune response through proliferation and differentiation of antibody secreting plasma cells. In a monocytic cell line, over-expression of BLIMP-1 can lead to differentiation into mature macrophages. BLIMP-1 also plays a role in osteoclastogenesis as well as in the modulation of dendritic cells. Other cells of the immune system such as human peripheral blood monocytes and granulocytes also express BLIMP-1.[6][10][11]

As a transcriptional repressor, BLIMP-1 has a critical role in the foundation of the mouse germ cell lineage, 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 of homeobox genes that normally accompany specification of primordial germ cells. BLIMP-1 is widely expressed in stem cells of developing embryos.[6] The genetic lineage-tracing experiments indicate that the BLIMP-1-positive cells originating from the proximal posterior epiblast cells 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 for naïve and memory B cells, all antibody secreting cells express BLIMP-1 regardless of their location and differentiation history.[5] BLIMP-1 directly initiates unfolded protein response (UPR) by activating Ire1, Xbp1, and Arf6, allowing the plasma B cells 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 of immunoglobulin.[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 of cytotoxic T-cell.[13] Specifically, the expression of granzyme 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 cell homeostasis. 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 in exhausted 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 in monocytes, inducing their differentiation into DCs and macrophages. It is speculated to have the similar effects in vivo.[6][9] In addition, BLIMP-1 also suppressed myeloid cells from differentiating into granulocytes, 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 with single nucleotide polymorphisms (SNP) near BLIMP-1 (specifically, rs548234 in Han Chinese, and rs6568431 in European) are predisposed to Systemic Lupus Erythematosus (SLE).[6][9]

Osteoclast development

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Osteoclasts are multinucleated cells that break down and resorb bone tissues.[6][18] Together with osteoblasts, which form new bones, osteoclast helps maintain and repair bone in vertebrates.[18] BLIMP-1 directly and indirectly represses anti-osteoclastogenesis genes such as Bcl6, IRF8, and MafB, 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]

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SNPs near the PRDM1 gene have been identified in genome-wide association studies (GWAS) to be linked to lupus (SLE) and rheumatoid arthritis (RA).[9] BLIMP-1 represses the expression of the proinflammatory cytokine Interleukin-6 (IL-6), and cathepsin S (CTSS), which promotes antigen processing and presentation. BLIMP-1 deficiency and IL-6 overexpression were linked to inflammatory bowel disease (IBD) and SLE.[6]

Another GWAS has identified two genetic variations near the PRDM1 gene that predict an increased likelihood of developing a second cancer after radiation treatment for Hodgkin lymphoma.[19]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000057657 – Ensembl, May 2017
  2. ^ a b c GRCm38: 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. ^ a b c d e Boi 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. PMID 25115512. S2CID 7518347.
  6. ^ a b c d e f g h i j k l m n o p q r s Ulmert 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. PMC 7692253. PMID 32799350.
  7. ^ a b c Wells 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. PMC 1088449. PMID 11375065.
  8. ^ a b c Crawford 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. PMC 3990591. PMID 24530057.
  9. ^ a b c d e f g h i Kim 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. PMC 4651792. PMID 26376898.
  10. ^ a b c d Turner, 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. ISSN 0092-8674. PMID 8168136. S2CID 46200658.
  11. ^ a b Sciammas 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. PMID 15100284.
  12. ^ a b Tellier 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. PMID 30273443. S2CID 52901472.
  13. ^ a b c d e f g Fu 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. PMC 5520377. PMID 28732506.
  14. ^ a b c Collier 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. PMC 9197228. PMID 34140679.
  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. PMID 15937476. S2CID 4399840.
  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. PMC 7744442. PMID 33176228.
  17. ^ Welsh RM (August 2009). "Blimp hovers over T cell immunity". Immunity. 31 (2): 178–180. doi:10.1016/j.immuni.2009.08.005. PMC 3220184. PMID 19699168.
  18. ^ a b Florencio-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. PMC 4515490. PMID 26247020.
  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. PMC 3229923. PMID 21785431.

Further reading

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This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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