TMEM39B

The TMEM39B gene in humans is located on the plus strand at 1p35.2. The gene is composed of 14 exons and covers 30.8 kb, spanning from 32,072,031 to 32,102,866. It is flanked by KHDRBS1 upstream and KPNA6 downstream. The TMEM39B gene region also contains the microRNA-encoding gene MIR5585.

There are four validated transcript variants for TMEM39B produced by different promoters and alternative splicing. Transcript variant 1 is translated into the longest and most abundant protein isoform.

File:Four validated transcript variants of TMEM39B.png

There are three validated protein isoforms for TMEM39B. Isoform 1 is the longest and the other two isoforms use a downstream in-frame start codon.

File:Transmembrane diagram of TMEM39B.pngThe human TMEM39B protein isoform 1 is composed of 492 amino acids and has a predicted molecular weight of 56 kDa. The basal isoelectric point (pI) of the protein is 9.51.{{Cite web|title=ExPASy - Compute pI/Mw tool|url=https://web.expasy.org/compute_pi/|access-date=2020-08-02|website=web.expasy.org}} Compared to the composition of the human proteome, TMEM39B has a higher percentage of serine, histidine, and leucine and a lower percentage of glutamate and aspartate, making it basic overall.{{cite journal |vauthors=Madeira F, Park YM, Lee J, et al. |title=The EMBL-EBI search and sequence analysis tools APIs in 2019 |journal=Nucleic Acids Research |date=2019 |volume=47 |issue=W1 |pages=W636–W641 |doi=10.1093/nar/gkz268 |doi-access=free |pmc=6602479 |pmid=30976793}} It contains two pairs of tandem repeats: “GSSG” from amino acids 21–28 and “PPSH” from amino acids 107–114. There is a periodic motif of four leucines spaced seven residues apart from amino acids 168–195, which is not predicted to form a leucine zipper. There is an “F..Y” motif with three repeats from amino acids 183-202 and a motif of phenylalanine at every other residue from amino acids 409–416. There are no notable charge clusters, charge runs, or spacings, nor are there any sorting signals.

TMEM39B isoform 1 contains eight transmembrane regions, and the N-terminus and C-terminus are predicted to be located in the cytosol.

File:Promoters of TMEM39B.png

TMEM39B has several promoter regions predicted by GenoMatix ElDorado.Genomatix: ElDorado. [https://www.genomatix.de/cgi-bin/eldorado/eldorado.pl?s=f7743f53d92d82020a1bef8ac7ee2d1b;SHOW_ANNOTATION=TMEM39B;ELDORADO_VERSION=E35R1911 TMEM39B] Most promoters are overlapping in a similar region, where use of a different promoter would only cause skipping of the first exon.

The promoter of TMEM39B transcript variant 1 contains numerous transcription factor binding sites. The transcription factors SMARCA3, TLX1, and CMYB have binding sites with high affinity near the binding site of transcription factor IIB, so they are potential regulators of gene transcription.

RNA sequencing data show that TMEM39B is expressed in all tissues types, with higher levels in the testis, placenta, white blood cells, adrenal gland, thymus, and fetal brain.{{cite journal |vauthors=Fagerberg L, Hallström BM, Oksvold P, et al |date=2014 |title=Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics |journal=Mol Cell Proteomics |volume=13 |issue=2 |pages=397–406 |doi=10.1074/mcp.M113.035600 |doi-access=free |pmc=3916642 |pmid=24309898}}{{Cite web |title=Illumina bodyMap2 transcriptome (ID 204271) - BioProject - NCBI |url=https://www.ncbi.nlm.nih.gov/bioproject/PRJEB2445/ |access-date=2020-07-30 |website=www.ncbi.nlm.nih.gov}} Microarray data show that TMEM39B is expressed at moderate levels in most tissues, on average in the 58th percentile of genes expressed in a given tissue sample.NCBI GEO (National Center for Biotechnology Gene Expression Omnibus) GDS596. TMEM39B. Su AI, Wiltshire T, Batalov S, Lapp H et al. A gene atlas of the mouse and human protein-encoding transcriptomes. Proc Natl Acad Sci U S A 2004 Apr 20;101(16):6062-7. {{PMID|15075390}} By percentile rank, TMEM39B is most highly expressed with respect to other genes in BDCA4+ dendritic cells, CD19+ B-cells, and CD14+ monocytes.

The 3' UTR of the TMEM39B protein contains binding sites for the miRNAs miR-1290, miR-4450, and miRNA-520d-5p.{{Cite web|title=miRDB - MicroRNA Target Prediction Database|url=http://mirdb.org/index.html|access-date=2020-07-30|website=mirdb.org}} Binding of these miRNAs may lead to RNA silencing.File:5' UTR of TMEM39B.png

File:3' UTR of TMEM39B transcript variant 1.png

The RNA-binding proteins SFRS13A, ELAVL1, and KHDRBS3 have binding sites in the 3' UTR, and the proteins KHSRP, SFRS9 and YBX1 have binding sites in the 5' UTR.{{Cite web|title=RBPDB: The database of RNA-binding specificities|url=http://rbpdb.ccbr.utoronto.ca/index.php|access-date=2020-08-02|website=rbpdb.ccbr.utoronto.ca}}{{Cite web|title=miRDB - MicroRNA Target Prediction Database|url=http://mirdb.org/index.html|access-date=2020-08-02|website=mirdb.org}}

The predicted secondary structure of the 5' and 3' UTR of TMEM39B contains multiple stem-loops which may play a role in stability and binding.

File:Conceptual translation of Homo sapiens TMEM39B.pdf

The TMEM39B protein contains numerous sites of predicted post-translational modifications, including phosphorylation, SUMOylation, acetylation, and glycosylation.{{cite journal |vauthors=Xie Y, Zheng Y, Li H, Luo X, He Z, Cao S, Shi Y, Zhao Q, Xue Y, Zuo Z, Ren J |date=2016 |title=GPS-Lipid: a robust tool for the prediction of multiple lipid modification sites |journal=Scientific Reports |volume=6 |page=28249 |doi=10.1038/srep28249 |doi-access=free |pmc=4910163 |pmid=27306108|bibcode=2016NatSR...628249X }}{{cite journal |vauthors=Ren J, Wen L, Gao X, Jin C, Xue Y, Yao X |date=2008 |title=CSS-Palm 2.0: an updated software for palmitoylation sites prediction |journal=Protein Engineering, Design & Selection |volume=21 |issue=11 |pages=639–644 |doi=10.1093/protein/gzn039 |doi-access=free |pmc=2569006 |pmid=18753194}}{{cite web |title=SUMOplot Analysis Program |publisher=Abcepta |url=https://www.abcepta.com/sumoplot}}{{cite journal |vauthors=Zhao Q, Xie Y, Zheng Y, Jiang S, Liu W, Mu W, Liu Z, Zhao Y, Xue Y, Ren J |date=2014 |title=GPS-SUMO: a tool for the prediction of sumoylation sites and SUMO-interaction motifs |journal=Nucleic Acids Research |volume=42 |issue=W1 |pages=W325–W330 |doi=10.1093/nar/gku383 |doi-access=free |pmc=4086084 |pmid=24880689}}{{cite journal |vauthors=Blom N, Gammeltoft S, Brunak S |date=1999 |title=Sequence and structure-based prediction of eukaryotic protein phosphorylation sites |journal=Journal of Molecular Biology |volume=294 |issue=5 |pages=1351–1362 |doi=10.1006/jmbi.1999.3310 |pmid=10600390}}{{cite journal |last1=Johansen |first1=Morten Bo |last2=Kiemer |first2=Lars |last3=Brunak |first3=Soren |date=2006 |title=Analysis and prediction of mammalian protein glycation |journal=Glycobiology |volume=16 |issue=9 |pages=844–853 |doi=10.1093/glycob/cwl009 |doi-access=free |pmid=16762979}}{{cite journal |vauthors=Steentoft C, Vakhrushev SY, Joshi HJ, Kong Y, Vester-Christensen MB, Schjoldager KT, Lavrsen K, Dabelsteen S, Pedersen NB, Marcos-Silva L, Gupta R, Bennett EP, Mandel U, Brunak S, Wandall HH, Levery SB, Clausen H |title=Precision mapping of the human O-GalNAc glycoproteome through SimpleCell technology |journal=EMBO J |volume=32 |issue=10 |pages=1478–88 |date=May 15, 2013 |doi= 10.1038/emboj.2013.79 |doi-access=free |pmc=3655468 |pmid=23584533}} Sites of predicted S-palmitoylation at Cys13, Cys87, and Cys264 are conserved in orthologs. SUMOylation is predicted at Lys279 and Lys359. Several well-conserved sites of phosphorylation, glycation, and O-linked-N-acetylglucosaminylation are predicted in cytosolic regions of the protein, as annotated on the conceptual translation of TMEM39B transcript variant 1.

The TMEM39B protein has been found to localize to the vesicles using immunohistochemistry.{{Cite web|title=Anti-TMEM39B antibody produced in rabbit HPA040191|url=https://www.sigmaaldrich.com/catalog/product/sigma/hpa040191|access-date=2020-07-30|website=Sigma-Aldrich}}

The human TMEM39B gene has a paralog called TMEM39A, also referred to by the alias SUSR2 (suppressor of SQST-1 aggregates in rpl-43 mutants), which is located at 3q13.33.{{Cite web|title=TMEM39A transmembrane protein 39A [Homo sapiens (human)] - Gene - NCBI|url=https://www.ncbi.nlm.nih.gov/gene/55254|access-date=2020-07-30|website=www.ncbi.nlm.nih.gov}} The TMEM39A protein contains 488 amino acids and shares 51.2% identity with TMEM39B.{{Cite web|last=|first=|date=|title=Standard Protein BLAST|url=https://blast.ncbi.nlm.nih.gov/Blast.cgi?PAGE=Proteins&PROGRAM=blastp&PAGE_TYPE=BlastSearch&BLAST_SPEC=|archive-url=|archive-date=|access-date=|website=National Center for Biotechnology Information.}} Although the function of the paralog TMEM39A is not well-understood, variants are associated with greater risk of autoimmune disease.{{cite journal |vauthors=Tran Q, Park J, Lee H, Hong Y, Hong S, Park S, Park J, Kim SH |date=2017 |title=TMEM39A and Human Diseases: A Brief Review |journal=Toxicological Research |volume=33 |issue=3 |pages=205–209 |doi=10.5487/TR.2017.33.3.205 |doi-access=free |pmc=5523561 |pmid=28744351|bibcode=2017ToxRe..33..205T }} The paralog TMEM39A has also been found to interact with Encephalomyocarditis virus (EMCV) capsid proteins as a regulator of the viral autophagy pathway.{{cite journal |vauthors=Li X, Ma R, Li Q, Li S, Zhang H, Xie J, Bai J, Idris A, Feng R |date=2019 |title=Transmembrane Protein 39A Promotes the Replication of Encephalomyocarditis Virus via Autophagy Pathway |journal=Frontiers in Microbiology |volume=10 |page=2680 |doi=10.3389/fmicb.2019.02680 |doi-access=free |pmc=6901969 |pmid=31849860}}

TMEM39B has orthologs in species as distant as cartilaginous fish. Mammalian orthologs are highly similar to human TMEM39B, with percent identity greater than 85%. In orthologs in birds, reptiles, and amphibians, the percent identity to human TMEM39B ranges between 70% and 85%. In fish, the percent identity ranges from 40% to 75%. TMEM39B is only conserved in vertebrates, but the paralog TMEM39A has orthologs in species as distant as arthropods. A selected list of orthologs from NCBI BLAST is displayed below.

The TMEM39B gene appears most distantly in cartilaginous fish (chondrichthyes), which diverged from humans approximately 465 million years ago.Kumar S, Stecher G, Suleski M, Hedges SB (2017) TimeTree: A Resource for Timelines, Timetrees, and Divergence Times. Mol Biol Evol doi:10.1093/molbev/msx116 Orthologs of the paralog TMEM39A are found in arthropods, which diverged from humans approximately 763 million years ago, suggesting that TMEM39B was produced by the duplication of an ancestral form of TMEM39A .

TMEM39B evolves at a relatively slow rate; a 1% change in the amino acid sequence requires approximately 13.9 million years. Based on sequence similarity of orthologs, TMEM39B evolves approximately 1.5 times faster than cytochrome c and 7 times slower than fibrinogen alpha.

Using co-immunoprecipitation, affinity capture MS, and two-hybrid screens, the TMEM39B protein has been found to interact with various membrane glycoproteins .{{cite journal |vauthors=Huttlin EL, Ting L, Bruckner RJ, et al |title=The BioPlex Network: A Systematic Exploration of the Human Interactome |journal=Cell |date=2015 |volume=162 |issue=2 |pages=425–440 |doi=10.1016/j.cell.2015.06.043 |pmc=4617211 |pmid=26186194}}{{cite journal |vauthors=Huttlin EL, Bruckner RJ, Paulo JA, et al |title=Architecture of the human interactome defines protein communities and disease networks |journal=Nature |date=2017 |volume=545 |issue=7655 |pages=505–509 |doi=10.1038/nature22366 |pmc=5531611 |pmid=28514442|bibcode=2017Natur.545..505H }}{{cite journal |vauthors=Wang J, Huo K, Ma L, et al |title=Toward an understanding of the protein interaction network of the human liver |journal=Mol Syst Biol |date=11 October 2011 |volume=7 |page=536 |doi=10.1038/msb.2011.67 |pmc=3261708 |pmid=21988832}} Many interacting proteins have immune functions, including IL13RA1 (interleukin-13 receptor subunit alpha-1), KLRD1 (killer cell lectin-like receptor subfamily D, member 1), and SEMA7A (semaphorin-7A). SEMA7A acts as an activator of T cells and monocytes, while KLDR1 encodes an antigen presented on natural killer cells.{{cite journal |vauthors=Xie J, Wang H |date=2017 |title=Semaphorin 7A as a potential immune regulator and promising therapeutic target in rheumatoid arthritis |journal=Arthritis Research & Therapy |volume=19 |issue=1 |page=10 |doi=10.1186/s13075-016-1217-5 |pmc=5251212 |pmid=28109308 |doi-access=free }}{{cite journal |last=Lanier |first=L. L. |date=2015 |title=KLRK1 (killer cell lectin-like receptor subfamily K, member 1) |journal=Atlas of Genetics and Cytogenetics in Oncology and Haematology |volume=19 |issue=3 |pages=172–175 |doi=10.4267/2042/56407 |doi-broken-date=25 December 2024 |hdl=2042/56407|hdl-access=free }} IL13RA1 has been proposed to mediate JAK-STAT signaling, which regulates immune cell activation.{{cite journal |vauthors=Sheikh F, Dickensheets H, Pedras-Vasconcelos J, et al |title=The Interleukin-13 Receptor-α1 Chain Is Essential for Induction of the Alternative Macrophage Activation Pathway by IL-13 but Not IL-4 |journal=Journal of Innate Immunity |date=2015 |volume=7 |issue=5 |pages=494–505 |doi=10.1159/000376579 |pmc=4553078 |pmid=25766112}}

The TMEM39B protein interacts with the SARS-CoV-2 ORF9c accessory protein, also sometimes referred to as ORF14.{{cite journal |last1=Shukla |first1=Aditi |last2=Hilgenfeld |first2=Rolf |name-list-style=vanc |date=2015 |title=Acquisition of new protein domains by coronaviruses: analysis of overlapping genes coding for proteins N and 9b in SARS coronavirus |journal=Virus Genes |volume=50 |issue=1 |pages=29–38 |doi=10.1007/s11262-014-1139-8 |pmc=7089080 |pmid=25410051}} ORF9C is located within the nucleocapsid (N) gene, overlapping with ORF9b. Two mutations in OFC9c resulting in premature stop codons have been observed in SARS-CoV-2 isolates, suggesting that this reading frame is dispensable for viral replication.von Brunn, A., Teepe, C., Simpson, J. C., Pepperkok, R., Friedel, C. C., Zimmer, R., ... & Haas, J. (2007). Analysis of intraviral protein-protein interactions of the SARS coronavirus ORFeome. PLOS ONE, 2(5), e459. The ORF9c protein has been shown to localize to vesicles when transfected into HeLa cells and is predicted to have a non-cytoplasmic domain and transmembrane domain.Baruah, C., Devi, P., & Sharma, D. K. (2020). Sequence analysis and structure prediction of SARS-CoV-2 accessory proteins 9b and ORF14: evolutionary analysis indicates close relatedness to bat coronavirus.

Many SNPs (single nucleotide polymorphisms) have been detected in the TMEM39B gene, of which a smaller subset cause nonsynonymous amino acid changes.{{Cite web|title=SNP linked to Gene (geneID:55116) Via Contig Annotation|url=https://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?geneId=55116&ctg=NT_032977.10&mrna=NM_018056.3&prot=NP_060526.2&orien=forward|access-date=2020-08-02|website=www.ncbi.nlm.nih.gov}} There are notably fewer SNPs that occur at sites of post-translational modifications, motifs, or highly conserved amino acids; changes in these amino acids may be more likely to have phenotypic effects. The table below lists selected SNPs resulting in a change at such sites.

In a study using 164 tumor samples from patients with diffuse large B cell lymphoma, TMEM39B was one of 17 genes identified as part of a prognostic profile for 5-year progression-free survival.{{cite journal |last1=Kim |display-authors=etal |date=2014 |title=Gene expression profiles for the prediction of progression-free survival in diffuse large B cell lymphoma: results of a DASL assay |journal=Annals of Hematology |volume=93 |issue=3 |pages=437–447 |doi=10.1007/s00277-013-1884-0 |pmid=23975159|s2cid=24280204 }} In another study using a genome-wide siRNA screen, knockdown of TMEM39B with siRNAs decreased viral capsid/autophagosome colocalization, survival of virus-infected cells, and mitophagy in HeLa cells infected with Sindbis virus.{{cite journal |last1=Orvedahl |display-authors=etal |date=2011 |title=Image-based genome-wide siRNA screen identifies selective autophagy factors |journal=Nature |volume=480 |issue=7375 |at=pp. 113–117, Figure 2 |doi=10.1038/nature10546 |pmc=3229641 |pmid=22020285|bibcode=2011Natur.480..113O }} This may suggest that TMEM39B plays a role in viral autophagy like its paralog TMEM39A.

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