Biology:PRDM1
Generic protein structure example |
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.[1] 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.[2][3][4] BLIMP-1 is a transcription factor that triggers expression of many downstream signaling cascades.[2][5][6][7] As a fine-tuned and contextual rheostat of the immune system, BLIMP-1 up- or down-regulates immune responses depending on the precise scenarios.[2][6][8] 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.[3][4][9][10]
Function
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.[2][5] 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.[2] 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.[2][5]
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.[2][6][7]
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.[2] 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.[11]
B cell development
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.[2][6] 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.[1] BLIMP-1 directly initiates unfolded protein response (UPR) by activating Ire1, Xbp1, and Atf6, allowing the plasma B cells to produce vast amounts of antibody.[2][8] 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.[12] BLIMP-1 is a direct transcriptional target of IRF-4, which is also necessary for B-cell differentiation.[2] 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.[1][9] 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.[1]
T cell development
BLIMP-1 promotes naive T-cells to differentiate into T-helper (Th) 2 lineage, while repressing the differentiation into Th1, Th17, and follicular Th.[5] BLIMP-1 is also required for differentiation of cytotoxic T-cell.[9] 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.[2][5]
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.[9] BLIMP-1 is important in dampening autoimmunity, as well as antiviral and antitumor responses.[9] 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.[1]
T cell exhaustion
Multiple studies have reported high expression of BLIMP-1 in exhausted T cells.[9][10] T cell exhaustion is usually a result of chronic immune activations, commonly caused by viral infection (e.g. HIV), cancer, or organ transplant.[3][9][10] 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.[4]
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.[13]
DCs and macrophages development
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.[2][5] In addition, BLIMP-1 also suppressed myeloid cells from differentiating into granulocytes, which includes eosinophil, basophil, and neutrophils.[2][5] 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).[2][5]
Osteoclast development
Osteoclasts are multinucleated cells that break down and resorb bone tissues.[2][14] Together with osteoblasts, which form new bones, osteoclast helps maintain and repair bone in vertebrates.[14] BLIMP-1 directly and indirectly represses anti-osteoclastogenesis genes such as Bcl6, IRF8, and MafB, helping monocytes differentiate into osteoclasts.[2] In mice, insufficient expression of BLIMP-1 in osteoclast progenitors would lead to abnormal development of the skeleton.[2]
SNPs near the PRDM1 gene have been identified in genome-wide association studies (GWAS) to be linked to lupus (SLE) and rheumatoid arthritis (RA).[5] 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.[2]
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.[15]
References
- ↑ 1.0 1.1 1.2 1.3 1.4 "PRDM1/BLIMP1: a tumor suppressor gene in B and T cell lymphomas". Leukemia & Lymphoma 56 (5): 1223–1228. May 2015. doi:10.3109/10428194.2014.953155. PMID 25115512.
- ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 2.18 "Mononuclear phagocyte regulation by the transcription factor Blimp-1 in health and disease". Immunology 161 (4): 303–313. December 2020. doi:10.1111/imm.13249. PMID 32799350.
- ↑ 3.0 3.1 3.2 "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. May 2001. doi:10.1098/rstb.2001.0845. PMID 11375065.
- ↑ 4.0 4.1 4.2 "Molecular and transcriptional basis of CD4⁺ T cell dysfunction during chronic infection". Immunity 40 (2): 289–302. February 2014. doi:10.1016/j.immuni.2014.01.005. PMID 24530057.
- ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 "Immunological function of Blimp-1 in dendritic cells and relevance to autoimmune diseases". Immunologic Research 63 (1–3): 113–120. December 2015. doi:10.1007/s12026-015-8694-5. PMID 26376898.
- ↑ 6.0 6.1 6.2 6.3 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" (in en). Cell 77 (2): 297–306. doi:10.1016/0092-8674(94)90321-2. ISSN 0092-8674. PMID 8168136. https://dx.doi.org/10.1016/0092-8674%2894%2990321-2.
- ↑ 7.0 7.1 "Modular nature of Blimp-1 in the regulation of gene expression during B cell maturation". Journal of Immunology 172 (9): 5427–5440. May 2004. doi:10.4049/jimmunol.172.9.5427. PMID 15100284.
- ↑ 8.0 8.1 "Plasma cells: The programming of an antibody-secreting machine". European Journal of Immunology 49 (1): 30–37. January 2019. doi:10.1002/eji.201847517. PMID 30273443.
- ↑ 9.0 9.1 9.2 9.3 9.4 9.5 9.6 "New insights into Blimp-1 in T lymphocytes: a divergent regulator of cell destiny and effector function". Journal of Biomedical Science 24 (1): 49. July 2017. doi:10.1186/s12929-017-0354-8. PMID 28732506.
- ↑ 10.0 10.1 10.2 "Not-so-opposite ends of the spectrum: CD8+ T cell dysfunction across chronic infection, cancer and autoimmunity". Nature Immunology 22 (7): 809–819. July 2021. doi:10.1038/s41590-021-00949-7. PMID 34140679.
- ↑ "Blimp1 is a critical determinant of the germ cell lineage in mice". Nature 436 (7048): 207–213. July 2005. doi:10.1038/nature03813. PMID 15937476. Bibcode: 2005Natur.436..207O.
- ↑ "Epigenetics of the antibody and autoantibody response". Current Opinion in Immunology. Autoimmunity 67: 75–86. December 2020. doi:10.1016/j.coi.2020.09.004. PMID 33176228.
- ↑ "Blimp hovers over T cell immunity". Immunity 31 (2): 178–180. August 2009. doi:10.1016/j.immuni.2009.08.005. PMID 19699168.
- ↑ 14.0 14.1 "Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells". BioMed Research International 2015: 421746. 2015-07-13. doi:10.1155/2015/421746. PMID 26247020.
- ↑ "Variants at 6q21 implicate PRDM1 in the etiology of therapy-induced second malignancies after Hodgkin's lymphoma". Nature Medicine 17 (8): 941–943. July 2011. doi:10.1038/nm.2407. PMID 21785431.
Further reading
- "Blimp-1 is the murine homolog of the human transcriptional repressor PRDI-BF1". Cell 78 (1): 9. July 1994. doi:10.1016/0092-8674(94)90565-7. PMID 8033216.
- "The B-lymphocyte maturation promoting transcription factor BLIMP1/PRDI-BF1 maps to D6S447 on human chromosome 6q21-q22.1 and the syntenic region of mouse chromosome 10". Genomics 37 (1): 24–28. October 1996. doi:10.1006/geno.1996.0516. PMID 8921366.
- "PRDI-BF1/Blimp-1 repression is mediated by corepressors of the Groucho family of proteins". Genes & Development 13 (1): 125–137. January 1999. doi:10.1101/gad.13.1.125. PMID 9887105.
- "Commitment of B lymphocytes to a plasma cell fate is associated with Blimp-1 expression in vivo". Journal of Immunology 165 (10): 5462–5471. November 2000. doi:10.4049/jimmunol.165.10.5462. PMID 11067898.
- "Stage-specific modulation of IFN-regulatory factor 4 function by Krüppel-type zinc finger proteins". Journal of Immunology 166 (10): 6104–6111. May 2001. doi:10.4049/jimmunol.166.10.6104. PMID 11342629.
- "The heterogeneity shown by human plasma cells from tonsil, blood, and bone marrow reveals graded stages of increasing maturity, but local profiles of adhesion molecule expression". Blood 99 (6): 2154–2161. March 2002. doi:10.1182/blood.V99.6.2154. PMID 11877292.
- "Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program". Immunity 17 (1): 51–62. July 2002. doi:10.1016/S1074-7613(02)00335-7. PMID 12150891.
- "Repression of AP-1 function: a mechanism for the regulation of Blimp-1 expression and B lymphocyte differentiation by the B cell lymphoma-6 protooncogene". Journal of Immunology 169 (4): 1922–1929. August 2002. doi:10.4049/jimmunol.169.4.1922. PMID 12165517.
- "Altered mRNA expression of Pax5 and Blimp-1 in B cells in multiple myeloma". Blood 100 (13): 4629–4639. December 2002. doi:10.1182/blood.V100.13.4629. PMID 12453881.
- "Identification of a functionally impaired positive regulatory domain I binding factor 1 transcription repressor in myeloma cell lines". Journal of Immunology 170 (6): 3125–3133. March 2003. doi:10.4049/jimmunol.170.6.3125. PMID 12626569.
- "PRDI-BF1 recruits the histone H3 methyltransferase G9a in transcriptional silencing". Nature Immunology 5 (3): 299–308. March 2004. doi:10.1038/ni1046. PMID 14985713.
- "Targeting positive regulatory domain I-binding factor 1 and X box-binding protein 1 transcription factors by multiple myeloma-reactive CTL". Journal of Immunology 175 (2): 1301–1309. July 2005. doi:10.4049/jimmunol.175.2.1301. PMID 16002735.
- "Mutational analysis of PRDM1 indicates a tumor-suppressor role in diffuse large B-cell lymphomas". Blood 107 (10): 4090–4100. May 2006. doi:10.1182/blood-2005-09-3778. PMID 16424392.
- "Inactivation of the PRDM1/BLIMP1 gene in diffuse large B cell lymphoma". The Journal of Experimental Medicine 203 (2): 311–317. February 2006. doi:10.1084/jem.20052204. PMID 16492805.
- "Immunization-induced perturbation of human blood plasma cell pool: progressive maturation, IL-6 responsiveness, and high PRDI-BF1/BLIMP1 expression are critical distinctions between antigen-specific and nonspecific plasma cells". Journal of Immunology 176 (7): 4042–4050. April 2006. doi:10.4049/jimmunol.176.7.4042. PMID 16547239.
- "PRDM1/BLIMP-1 expression in multiple B and T-cell lymphoma". Haematologica 91 (4): 467–474. April 2006. PMID 16585013.
- "A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration". Cell 125 (4): 801–814. May 2006. doi:10.1016/j.cell.2006.03.032. PMID 16713569.
External links
- PRDM1+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH)
- FactorBook PRDM1
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
Original source: https://en.wikipedia.org/wiki/PRDM1.
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