 | This article may be too technical for most readers to understand.(December 2023) |
Highly Expressed In Immature Dendritic Cell Transcript 1 (HIDE1) is a protein encoded by chromosome 19 open reading frame 38 (C19orf38) gene in humans. [1] There are no other aliases used for the gene. C19orf38 is only expressed in white blood cells, of the innate immune system. HIDE1 protein has been found to play a role in immune escape of tumors and diet induced obesity.
C19orf38 is cytogenetically banded at 19p13.2 spanning 33,216 base pairs oriented on the forward strand (chr19:+10,947,251 to +10,980,466). C19orf38 is located near the following genes: TMED1, HSALNG0123968, ZNF627, and KRIT1.
There are five risk associated variants found within the c19orf38 gene. Three of which lead to a significant increase in low density lipoprotein cholesterol. [2] [3] One variant is associated with prevalence of coronary artery disease. [4] And the fifth identified risk variant is associated with increased reporting of Idiopathic knee osteoarthritis. [5]
C19orf38 can be alternatively spliced to form three distinct mRNA products. Both isoform's 1 and 2 differ only via the 5' UTR. Isoform 3 has a different protein product in that the mRNA transcript does not contain exon 2 or exon 3, however, isoform 3 is not expressed in humans.
C19orf38 transcript is found at the highest amount in bone marrow, with less than a fifth of the transcript amount in the spleen, testis, appendix, and lymph nodes, with little to no transcript in other tissue types. Tissues with the transcript have a high leukocyte presence. [6] It is exclusively present in the following cell types: monocytes, peripheral blood mononuclear cells, eosinophils and basophil's, so any expression in tissues comes from innate immune cells, or granulocytes. [7] Transcript is not present in neutrophils. C19orf38 transcript is not found in macrophages, despite, classical monocyte expression. [8]
The promoter region of C19orf38 contains two transcription factor binding domains that are particularly important for innate immune system development: Spi-C Transcription Factor (SPIC) and E74 Like ETS Transcription Factor 3 (ELF3). Both are transcription factors are only present in leukocytes are involved in the negative transcription of genes for the development of macrophages, which coincides with cellular localization of C19orf38. [9]
HIDE1 is a 230 amino acid transmembrane protein, anchored via ɑ-helix transmembrane region. F-box only protein 2 (FBXO2) binds in an extracellular region to glycosylated arginine amino acids found at positions 48 and 97. [11] The extracellular region also contains a highly conserved signal peptide sequence, which leads the protein to the membrane space. Additionally, HIDE1 protein contains a disordered region in its intracellular region. TNPO3 and XPO-4 are known to interact with HIDE1. [12]
Human HIDE1 protein is largely confirmed to be a signal protein existing either embedded within the cellular membrane or in a secreted form. Deeploc signal analysis predicts a signal peptide region at the start of its translation. [13] Furthermore, PSORT2 k-NN prediction finds the protein to be localized extracellularly 34.8% of the time, 30.4% in the plasma membrane, 21.7% in the endoplasmic reticulum, and 13.0% in the golgi bodies. [14]
HIDE1 protein contains an ig-like domain and signal peptide in its extracellular region as well as multiple lipidification sites to assist with membrane association. [15] [16] Additionally, N-linked glycosylation sites can be found in the luminal side. The intracellular/cytoplasmic region contains multiple phosphorylation sites and calpain cleavage locations. [17]
Orthologs are found in the following taxon classes: Mammalia, Reptilia, Aves, and Amphibia. There are no orthologs found in either class insecta or actinopterygii. C19orf38 is only present in jawed vertebrates which coincides with the divergence of adaptive immune systems 550 MYA between jawed and jawless vertebrates.
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C19orf38 mutation rate is found to be less than that of fibrinogen alpha, but is high in comparison to other human proteins, especially, immune proteins which are highly conserved in jawed vertebrates. [20]
Theodros reveals protein HIDE1 role in host homeostasis, in addition to interactions with myeloid cells which often interact with tumor development. [21] Lastly, Theodoros shows that HIDE1 accomplishes both through acting as an upstream signal to induce Trem2 myeloid signature, a unique transcriptional portrayal. Trem2 activation allows for immune escape by the tumor, thus acting as a crucial regulator in antitumor immune response. Blocking transcription of C19orf38 or preventing HIDE1 activation may be a novel approach to avoid immune escape by various tumors.
Despite these findings, HIDE1 shows no significant association with any cancer. [22]
Xiaoxu’s dissertation examines HIDE1’s interaction with diet induced obesity. It was found that HIDE1 plays a critical role in weight gain, in that, deletion of c19orf38 resulted in a gain of weight. [11] This allows for potential use for drug treatment therapies to block activity of HIDE1 to control weight gain.
CD16, also known as FcγRIII, is a cluster of differentiation molecule found on the surface of natural killer cells, neutrophils, monocytes, macrophages, and certain T cells. CD16 has been identified as Fc receptors FcγRIIIa (CD16a) and FcγRIIIb (CD16b), which participate in signal transduction. The most well-researched membrane receptor implicated in triggering lysis by NK cells, CD16 is a molecule of the immunoglobulin superfamily (IgSF) involved in antibody-dependent cellular cytotoxicity (ADCC). It can be used to isolate populations of specific immune cells through fluorescent-activated cell sorting (FACS) or magnetic-activated cell sorting, using antibodies directed towards CD16.
The granulocyte-macrophage colony-stimulating factor receptor, also known as CD116, is a receptor for granulocyte-macrophage colony-stimulating factor, which stimulates the production of white blood cells. In contrast to M-CSF and G-CSF which are lineage specific, GM-CSF and its receptor play a role in earlier stages of development. The receptor is primarily located on neutrophils, eosinophils and monocytes/macrophages, it is also on CD34+ progenitor cells (myeloblasts) and precursors for erythroid and megakaryocytic lineages, but only in the beginning of their development.
EGF-like module-containing mucin-like hormone receptor-like 3 is a protein encoded by the ADGRE3 gene. EMR3 is a member of the adhesion GPCR family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.
Programmed death-ligand 1 (PD-L1) also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1) is a protein that in humans is encoded by the CD274 gene.
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Colony stimulating factor 1 receptor (CSF1R), also known as macrophage colony-stimulating factor receptor (M-CSFR), and CD115, is a cell-surface protein encoded by the human CSF1R gene. CSF1R is a receptor that can be activated by two ligands: colony stimulating factor 1 (CSF-1) and interleukin-34 (IL-34). CSF1R is highly expressed in myeloid cells, and CSF1R signaling is necessary for the survival, proliferation, and differentiation of many myeloid cell types in vivo and in vitro. CSF1R signaling is involved in many diseases and is targeted in therapies for cancer, neurodegeneration, and inflammatory bone diseases.
CD47 also known as integrin associated protein (IAP) is a transmembrane protein that in humans is encoded by the CD47 gene. CD47 belongs to the immunoglobulin superfamily and partners with membrane integrins and also binds the ligands thrombospondin-1 (TSP-1) and signal-regulatory protein alpha (SIRPα). CD-47 acts as a don't eat me signal to macrophages of the immune system which has made it a potential therapeutic target in some cancers, and more recently, for the treatment of pulmonary fibrosis.
CD244 also known as 2B4 or SLAMF4 is a protein that in humans is encoded by the CD244 gene.
5′-nucleotidase (5′-NT), also known as ecto-5′-nucleotidase or CD73, is an enzyme that in humans is encoded by the NT5E gene. CD73 commonly serves to convert AMP to adenosine.
OX-2 membrane glycoprotein, also named CD200 is a human protein encoded by the CD200 gene. CD200 gene is in human located on chromosome 3 in proximity to genes encoding other B7 proteins CD80/CD86. In mice CD200 gene is on chromosome 16.
Triggering receptor expressed on myeloid cells 2(TREM2) is a protein that in humans is encoded by the TREM2 gene. TREM2 is expressed on macrophages, immature monocyte-derived dendritic cells, osteoclasts, and microglia, which are immune cells in the central nervous system. In the liver, TREM2 is expressed by several cell types, including macrophages, that respond to injury. In the intestine, TREM2 is expressed by myeloid-derived dendritic cells and macrophage. TREM2 is overexpressed in many tumor types and has anti-inflammatory activities. It might therefore be a good therapeutic target.
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Chromosome 19 open reading frame 18 (c19orf18) is a protein which in humans is encoded by the c19orf18 gene. The gene is exclusive to mammals and the protein is predicted to have a transmembrane domain and a coiled coil stretch. This protein has a function that is not yet fully understood by the scientific community.
Retroelement silencing factor 1 is a protein that in humans is encoded by the RESF1 gene. RESF1 is broadly expressed in the lymph nodes, ovaries, appendix and spleen. RESF1 shows characteristics of being a minor histocompatibility antigen, as well as tumor suppressor capabilities. The high expression in the lymph nodes and spleen indicate function in the immune system.
WD Repeat and Coiled-coiled containing protein (WDCP) is a protein which in humans is encoded by the WDCP gene. The function of the protein is not completely understood, but WDCP has been identified in a fusion protein with anaplastic lymphoma kinase found in colorectal cancer. WDCP has also been identified in the MRN complex, which processes double-stranded breaks in DNA.
Synaptosome-associated protein, 47 kDal (SNAP47) is a human protein encoded by the SNAP47 gene. Other aliases of this gene are SVAP1, HEL170, ESFI5812, and HEL-S-290. SNAP47 is a synaptosome protein which is associated with the protein coding in multiple diseases, including non small cell lung cancer and schizophrenia. SNAP47 is a member of the SNAP protein family. SNAP proteins are t-snare proteins that are a component of SNARE complex. The SNARE complex mediates vesicle fusion by creating tight complex that brings vesicle and membrane together. This protein causes ubiquitous expression in testis, ovary, and many other tissues
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SERTM2, also known as the Serine Rich And Transmembrane Domain Containing 2, is a protein which in humans is encoded by the SERTM2 gene. The SERTM2 protein is a transmembrane protein located in the intracellular membrane and active in membrane-bound organelles. SERTM2 expression has been linked to metastatic prostate tumors, prostate carcinomas and renal cell carcinomas.