C19orf38

Highly Expressed In Immature Dendritic Cell Transcript 1 (HIDE1) is a protein encoded by chromosome 19 open reading frame 38 (C19orf38) gene in humans. 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.

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.  One variant is associated with prevalence of coronary artery disease. And the fifth identified risk variant is associated with increased reporting of Idiopathic knee osteoarthritis.

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. 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. Transcript is not present in neutrophils. C19orf38 transcript is not found in macrophages, despite, classical monocyte expression.

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.

Structure
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. 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.

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. 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.

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. Additionally, N-linked glycosylation sites can be found in the luminal side. The intracellular/cytoplasmic region contains multiple phosphorylation sites and calpain cleavage locations.

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.

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.

Clinical significance
Theodros reveals protein HIDE1 role in host homeostasis, in addition to interactions with myeloid cells which often interact with tumor development. 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.

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. This allows for potential use for drug treatment therapies to block activity of HIDE1 to control weight gain.