Biology:C19orf38

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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.

Gene

C19orf38 location on chromosome 19, gene neighborhood, and gene overview.

Location

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.

Risk-associated variants

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]

mRNA Transcripts

Isoforms

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.

Tissue Localization

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]

Regulation of Transcription

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]

Protein

Structure

HIDE1 protein three-dimensional structure.[10]

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]

Sub-cellular localization

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]

Binding motifs

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]

Human Protein HIDE1 domain, motif, and post translational modification diagram.

Homology

Orthologs

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.

Table of C19orf38 transcript orthologs and related properties. Data is organized by median date of divergence (MYA), and then sequence identity to Homo sapien (Hsa) protein.[18][19]
human C19orf38 unrooted evolutionary tree.

Evolutionary rate

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]

Clinical significance

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.

References

  1. ↑ "C19orf38 chromosome 19 open reading frame 38 [Homo sapiens (human) - Gene - NCBI"]. https://www.ncbi.nlm.nih.gov/gene/255809. 
  2. ↑ Sinnott-Armstrong, Nasa; Tanigawa, Yosuke; Amar, David; Mars, Nina; Benner, Christian; Aguirre, Matthew; Venkataraman, Guhan Ram; Wainberg, Michael et al. (February 2021). "Genetics of 35 blood and urine biomarkers in the UK Biobank". Nature Genetics 53 (2): 185–194. doi:10.1038/s41588-020-00757-z. ISSN 1546-1718. PMID 33462484. 
  3. ↑ Lee, Sung-Bum; Choi, Ja-Eun; Park, Byoungjin; Cha, Mi-Yeon; Hong, Kyung-Won; Jung, Dong-Hyuk (2022-07-06). "Dyslipidaemia-Genotype Interactions with Nutrient Intake and Cerebro-Cardiovascular Disease". Biomedicines 10 (7): 1615. doi:10.3390/biomedicines10071615. ISSN 2227-9059. PMID 35884923. 
  4. ↑ Patrick, Matthew T.; Li, Qinmengge; Wasikowski, Rachael; Mehta, Nehal; Gudjonsson, Johann E.; Elder, James T.; Zhou, Xiang; Tsoi, Lam C. (2022-11-02). "Shared genetic risk factors and causal association between psoriasis and coronary artery disease". Nature Communications 13 (1): 6565. doi:10.1038/s41467-022-34323-4. ISSN 2041-1723. PMID 36323703. Bibcode: 2022NatCo..13.6565P. 
  5. ↑ Hollis, B.; Chatzigeorgiou, C.; Southam, L.; Hatzikotoulas, K.; Kluzek, S.; Williams, A.; Genetics of Osteoarthritis Consortium; Zeggini, E. et al. (October 2023). "Lifetime risk and genetic predisposition to post-traumatic OA of the knee in the UK Biobank". Osteoarthritis and Cartilage 31 (10): 1377–1387. doi:10.1016/j.joca.2023.05.012. ISSN 1522-9653. PMID 37247657. 
  6. ↑ "C19orf38 Gene Expression - Gene - NCBI". https://www.ncbi.nlm.nih.gov/gene/255809?report=expression&bioproject=PRJEB2445. 
  7. ↑ "Immune cell - C19orf38 - The Human Protein Atlas". https://www.proteinatlas.org/ENSG00000214212-C19orf38/immune+cell. 
  8. ↑ Maouche, Seraya; Poirier, Odette; Godefroy, Tiphaine; Olaso, Robert; Gut, Ivo; Collet, Jean-Phillipe; Montalescot, Gilles; Cambien, François (2008-06-25). "Performance comparison of two microarray platforms to assess differential gene expression in human monocyte and macrophage cells". BMC Genomics 9: 302. doi:10.1186/1471-2164-9-302. ISSN 1471-2164. PMID 18578872. 
  9. ↑ Carlsson, Robert; Hjalmarsson, Anna; Liberg, David; Persson, Christine; Leanderson, Tomas (2002-10-16). "Genomic structure of mouse SPI-C and genomic structure and expression pattern of human SPI-C". Gene 299 (1–2): 271–278. doi:10.1016/s0378-1119(02)01078-8. ISSN 0378-1119. PMID 12459275. https://pubmed.ncbi.nlm.nih.gov/12459275/. 
  10. ↑ "AlphaFold Protein Structure Database". https://alphafold.ebi.ac.uk/. 
  11. ↑ 11.0 11.1 Wang, Xiaoxu (2023-03-27). CGEN009/JHU001 IS A NOVEL REGULATOR OF OBESITY AND METABOLISM (Thesis). Johns Hopkins University.
  12. ↑ Diaz, Connor; G. Thankam, Finosh; K. Agrawal, Devendra (2023). "Karyopherins in the Remodeling of Extracellular Matrix: Implications in Tendon Injury". Journal of Orthopaedics and Sports Medicine 05 (3): 357–374. doi:10.26502/josm.511500122. PMID 37829147. PMC 10569131. https://www.fortunejournals.com/articles/karyopherins-in-the-remodeling-of-extracellular-matrix-implications-in-tendon-injury.html. 
  13. ↑ "DeepLoc 2.0 - DTU Health Tech - Bioinformatic Services" (in en). https://services.healthtech.dtu.dk/services/DeepLoc-2.0/. 
  14. ↑ "PSORT II Prediction". https://psort.hgc.jp/form2.html. 
  15. ↑ "Motif Scan" (in en). https://myhits.sib.swiss/cgi-bin/motif_scan. 
  16. ↑ "ELM - Search the ELM resource" (in en). http://elm.eu.org/. 
  17. ↑ "PhosphoSitePlus". https://www.phosphosite.org/homeAction.action. 
  18. ↑ "BLAST: Basic Local Alignment Search Tool". https://blast.ncbi.nlm.nih.gov/Blast.cgi. 
  19. ↑ "EMBOSS Needle < Pairwise Sequence Alignment < EMBL-EBI". https://www.ebi.ac.uk/Tools/psa/emboss_needle/. 
  20. ↑ Cooper, Max D.; Alder, Matthew N. (February 2006). "The Evolution of Adaptive Immune Systems". Cell 124 (4): 815–822. doi:10.1016/j.cell.2006.02.001. ISSN 0092-8674. PMID 16497590. 
  21. ↑ Theodros, Debebe; Murter, Benjamin M.; Sidhom, John-William; Nirschl, Thomas R.; Clark, David J.; Chen, LiJun; Tam, Ada J.; Blosser, Richard L. et al. (November 2020). "High-dimensional Cytometry (ExCYT) and Mass Spectrometry of Myeloid Infiltrate in Clinically Localized Clear Cell Renal Cell Carcinoma Identifies Novel Potential Myeloid Targets for Immunotherapy". Molecular & Cellular Proteomics 19 (11): 1850–1859. doi:10.1074/mcp.ra120.002049. ISSN 1535-9476. PMID 32737216. 
  22. ↑ "Expression of C19orf38 in cancer - Summary - The Human Protein Atlas". https://www.proteinatlas.org/ENSG00000214212-C19orf38/pathology. 



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