PRDM1

Last updated
PRDM1
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases PRDM1 , BLIMP1, PRDI-BF1, PR domain 1, PR/SET domain 1
External IDs OMIM: 603423 MGI: 99655 HomoloGene: 925 GeneCards: PRDM1
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 Mb Chr 10: 44.31 – 44.4 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/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

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. The regulatory role of BLIMP-1 on immunocytokines and hematopoietic cells.png
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

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

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

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

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

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]

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]

Related Research Articles

<span class="mw-page-title-main">Memory B cell</span> Cell of the adaptive immune system

In immunology, a memory B cell (MBC) is a type of B lymphocyte that forms part of the adaptive immune system. These cells develop within germinal centers of the secondary lymphoid organs. Memory B cells circulate in the blood stream in a quiescent state, sometimes for decades. Their function is to memorize the characteristics of the antigen that activated their parent B cell during initial infection such that if the memory B cell later encounters the same antigen, it triggers an accelerated and robust secondary immune response. Memory B cells have B cell receptors (BCRs) on their cell membrane, identical to the one on their parent cell, that allow them to recognize antigen and mount a specific antibody response.

<span class="mw-page-title-main">CD154</span> Protein-coding gene in humans

CD154, also called CD40 ligand or CD40L, is a protein that is primarily expressed on activated T cells and is a member of the TNF superfamily of molecules. It binds to CD40 on antigen-presenting cells (APC), which leads to many effects depending on the target cell type. In total CD40L has three binding partners: CD40, α5β1 integrin and integrin αIIbβ3. CD154 acts as a costimulatory molecule and is particularly important on a subset of T cells called T follicular helper cells. On TFH cells, CD154 promotes B cell maturation and function by engaging CD40 on the B cell surface and therefore facilitating cell-cell communication. A defect in this gene results in an inability to undergo immunoglobulin class switching and is associated with hyper IgM syndrome. Absence of CD154 also stops the formation of germinal centers and therefore prohibiting antibody affinity maturation, an important process in the adaptive immune system.

<span class="mw-page-title-main">CD20</span> Mammalian protein found in Homo sapiens

B-lymphocyte antigen CD20 or CD20 is expressed on the surface of all B-cells beginning at the pro-B phase and progressively increasing in concentration until maturity.

<span class="mw-page-title-main">Interleukin 21</span> Mammalian protein found in humans

Interleukin 21 (IL-21) is a protein that in humans is encoded by the IL21 gene.

Chemokine ligand 1 (CCL1) is also known as small inducible cytokine A1 and I-309 in humans. CCL1 is a small glycoprotein that belongs to the CC chemokine family.

<span class="mw-page-title-main">CD19</span> Biomarker for B cell lineage

B-lymphocyte antigen CD19, also known as CD19 molecule, B-Lymphocyte Surface Antigen B4, T-Cell Surface Antigen Leu-12 and CVID3 is a transmembrane protein that in humans is encoded by the gene CD19. In humans, CD19 is expressed in all B lineage cells. Contrary to some early doubts, human plasma cells do express CD19, as confirmed by others. CD19 plays two major roles in human B cells: on the one hand, it acts as an adaptor protein to recruit cytoplasmic signaling proteins to the membrane; on the other, it works within the CD19/CD21 complex to decrease the threshold for B cell receptor signaling pathways. Due to its presence on all B cells, it is a biomarker for B lymphocyte development, lymphoma diagnosis and can be utilized as a target for leukemia immunotherapies.

CD70 is a protein that in humans is encoded by CD70 gene. CD70 is also known as a ligand for CD27.

<span class="mw-page-title-main">Toll-like receptor 10</span> Protein-coding gene in the species Homo sapiens

Toll-like receptor 10 is a protein that in humans is encoded by the TLR10 gene. TLR10 has also been designated as CD290 . TLR10 has not been extensively studied because it is a pseudogene in mice, though all other mammalian species contain an intact copy of the TLR10 gene. Unlike other TLRs, TLR10 does not activate the immune system and has instead been shown to suppress inflammatory signaling on primary human cells. This makes TLR10 unique among the TLR family. TLR10 was thought to be an "orphan" receptor, however, recent studies have identified ligands for TLR10 and these include HIV-gp41. Ligands for TLR2 are potential ligands for TLR10.

<span class="mw-page-title-main">BCL6</span> Transcription factor for converting Naive T cells to TFH

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<span class="mw-page-title-main">CD83</span>

CD83 is a human protein encoded by the CD83 gene.

<span class="mw-page-title-main">CD69</span>

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<span class="mw-page-title-main">GPR183</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">PAX5</span> Protein-coding gene in humans

Paired box protein Pax-5 is a protein that in humans is encoded by the PAX5 gene.

<span class="mw-page-title-main">IRF4</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">SLAMF1</span> Protein-coding gene in humans

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<span class="mw-page-title-main">IKZF3</span> Protein-coding gene in the species Homo sapiens

Zinc finger protein Aiolos also known as Ikaros family zinc finger protein 3 is a protein that in humans is encoded by the IKZF3 gene.

<span class="mw-page-title-main">Lymphocyte-activation gene 3</span>

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<span class="mw-page-title-main">KLF13</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">ZBTB32</span> Protein-coding gene in the species Homo sapiens

Zinc finger and BTB domain-containing protein 32 is a protein that in humans is encoded by the 1960 bp ZBTB32 gene. The 52 kDa protein is a transcriptional repressor and the gene is expressed in T and B cells upon activation, but also significantly in testis cells. It is a member of the Poxviruses and Zinc-finger (POZ) and Krüppel (POK) family of proteins, and was identified in multiple screens involving either immune cell tumorigenesis or immune cell development.

<span class="mw-page-title-main">CD79A</span> Mammalian protein found in Homo sapiens

Cluster of differentiation CD79A also known as B-cell antigen receptor complex-associated protein alpha chain and MB-1 membrane glycoprotein, is a protein that in humans is encoded by the CD79A gene.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000057657 - Ensembl, May 2017
  2. 1 2 3 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.
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  18. 1 2 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.

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