RTL6

Retrotransposon Gag Like 6 is a protein encoded by the RTL6 gene in humans.^[5] RTL6 is a member of the Mart family of genes, which are related to Sushi-like retrotransposons and were derived from fish and amphibians.^[6] The RTL6 protein is localized to the nucleus and has a predicted leucine zipper motif that is known to bind nucleic acids in similar proteins, such as LDOC1.

RTL6
Identifiers
Aliases	RTL6, Mar6, Mart6, dJ1033E15.2, LDOC1L, leucine zipper, down-regulated in cancer 1-like, leucine zipper, down-regulated in cancer 1 like, LDOC1 like, SIRH3, retrotransposon Gag like 6
External IDs	MGI: 2675858; HomoloGene: 18594; GeneCards: RTL6; OMA:RTL6 - orthologs
Gene location (Human) Chr. Chromosome 22 (human)[1] Band 22q13.31 Start 44,492,583 bp[1] End 44,498,233 bp[1]
Gene location (Mouse) Chr. Chromosome 15 (mouse)[2] Band 15|15 E2 Start 84,437,599 bp[2] End 84,442,024 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in endothelial cell tibialis anterior muscle mucosa of ileum pancreatic epithelial cell myocardium of left ventricle ganglionic eminence pancreatic ductal cell cardiac muscle tissue of right atrium middle temporal gyrus ventricular zone Top expressed in saccule otic vesicle perirhinal cortex entorhinal cortex ganglionic eminence CA3 field medial ganglionic eminence habenula visual cortex olfactory epithelium More reference expression data BioGPS n/a
Orthologs Species Human Mouse Entrez 84247 223732 Ensembl ENSG00000188636 ENSMUSG00000055745 UniProt Q6ICC9 Q505G4 RefSeq (mRNA) NM_032287 NM_177630 RefSeq (protein) NP_115663 NP_808298 Location (UCSC) Chr 22: 44.49 – 44.5 Mb Chr 15: 84.44 – 84.44 Mb PubMed search [3] [4]
Wikidata
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Gene

Locus

Gene neighborhood of RTL6 on chromosome 22.^[5]

The gene is on Chromosome 22 (human) at 22q13.31 on the minus strand from 44492570 to 44498125 nt on the GRCh38.p7 assembly of the human genome. Aliases for the gene include LDOC1L, MAR6, MART6, and SIRH3. RTL6 is made up of 2 exons and is encoded by 5556 base pairs of DNA .^[7]

Origin

RTL6 is a retrotransposon GAG related gene. It is one of eleven MART (Mammalian Retrotransposon Derived) genes in humans related to Sushi-like retrotransposons with long terminal repeats from fish and amphibians.^[6] Between 170 and 310 MYA, MART genes lost their ability to retrotranspose and concomitantly gained new, beneficial function for its host organism.^[8]

mRNA

RTL6 has an alternate start of transcription 140 base pairs upstream of the normal transcribed region. The lengths of the primary mRNA and that with the upstream start of transcription are 5355 and 5495 base pairs respectively.^[7]

Protein

Primary information

The primary amino acid sequence for RTL6 is made up of 239 residues.^[5] There are no known alternative splice variants of the protein. The molecular weight of the protein is 26.2 kDa and the isoelectric point is 11.58.^[9] RTL6 is a proline and arginine rich protein.^[9]

I-TASSER predicted secondary and tertiary structures for the RTL6 protein.^[10][11][12]

Immunohistochemical staining of human stomach shows strong nuclear and cytoplasmic positivity in glandular cells.^[13]

Domains and motifs

RTL6 contains a predicted leucine zipper motif known to participate in nucleic acid binding in other proteins.^[9] RTL6 also contains a domain of unknown function from amino acid residues 98-177 . RTL6 is one of a number of genes belonging to the DUF4939 (domain of unknown function) superfamily.^[14]

Secondary structure

The secondary structure of RTL6 is made up of largely alpha helices.^[15] One region of RTL6 is also predicted to participate in a coiled-coil structure from amino acid residues 29–63.^[14]

Post-translational modifications

There are also two predicted phosphorylation sites for Protein Kinase C with high confidence scores at amino acid residues 6 and 45.^[16][17] There is also a predicted ubiquitination site with medium-confidence at amino acid residue 8.^[18]

An annotated schematic of the RTL6 protein showing motifs and predicted phosphorylation and ubiquitination sites.

Cellular sublocation

RTL6 is expected to be localized to the nucleus and cytosol based on the presence of a leucine zipper domain, the absence of signals indicating secretion or transmembrane domains, and immunohistochemical staining.^[19][20][21]

Expression

RTL6 has been shown to be expressed at high levels during all stages of development and in a wide variety of tissues.^[22][23][13]

RTL6 expression has been shown to fall in HeLa cervical cancer cells upon treatment with chemotherapeutic Casiopeinas and in A549 lung cancer cells upon treatment with Actinomycin D.^[24][25]

Interacting proteins

RTL6 has been shown to interact with the following proteins:

DDIT3	DNA damage-inducible transcript 3 protein [26]
NXF1	Nuclear RNA export factor 1 [27]
STX18	Syntaxin 18 [28]
MAFF	MAF bZIP transcription factor F [28]
GOPC	Golgi-associated PDZ and coiled-coil motif-containing protein [28]
BATF3	Basic leucine zipper transcriptional factor ATF-like 3 [28]
TERF2	Telomeric repeat-binding factor 2 [29]
UXAC	Uronate isomerase (Yersinia pestis) [30]

Clinical significance

The RTL6 protein has been shown to interact with the UXAC protein from Yersinia pestis, the gram-negative bacterium responsible for the bubonic plague.^[30]

Homology/evolution

Paralogs

Eleven paralogs were identified for RTL6 in humans. The paralogs have diverse functions and expression patterns, although many are known to have zinc finger domains and bind nucleic acids:

MART Family Name	Accession Number	Sequence Length	Query Cover	Percent Similarity
RTL1 [31]	NP_001128360.1	1358	100	7.6
PEG10 (RTL2) [32]	NP_055883.2	359	35	35
RTL3 [33]	NP_689907.1	2648	100	2.2
RTL4 [34]	NP_001004308.2	310	100	19
RTL5 [35]	NP_001019626.1	569	37	53
RTL6 [5]	NP_115663.2	239	NA	NA
LDOC1 (RTL7) [36]	NP_036449.1	146	33	41
RTL8A [37]	NP_001071640.1	113	33	44
RTL8B [38]	NP_001071641.1	113	33	43
RTL8C [39]	NP_001071639.1	113	33	44
RTL9 [40]	NP_065820.1	1388	22	39
RTL10 [41]	NP_078903.3	364	34	35

Orthologs

RTL6 is highly conserved across mammals, including the leucine zipper motif and DUF4939. The gene is also conserved in marsupials such as the opossum but not in birds such as the chicken, suggesting the gene was likely formed after the divergence of mammals and birds but before the divergence of marsupials and mammals (170-310 MYA:^[6]

Organism	Common Name	Classification	Accession Number	Percent Identity	Query Cover	Percent Similarity
Homo sapiens	Humans	Primate	NP_115663.2 [5]	NA	NA	NA
Macaca mulatta	Rhesus Monkey	Primate	NP_001181372.1 [42]	98	100	99
Felis catus	House Cat	Carnivore	XP_003989415.1 [43]	97	100	98
Mus muscalus	Common Mouse	Rodent	NP_808298.2 [44]	92	100	96
Pteropus alecto	Black Flying Fox	Bat	XP_006917396.1 [45]	96	100	98
Equus caballus	Horse	Odd-Toed Ungulates	XP_005606827.1 [46]	95	100	98
Bos Taurus	Cattle	Even-Toed Ungulates	XP_015326927.1 [47]	94	100	97
Orcinus orca	Killer Whale	Whales/Dolphins	XP_004279624.1 [48]	95	100	98
Trichechus manatus latirostirs	Florida Manatee	Placentals	XP_004380056.1 [49]	95	100	96
Erinaceus europaeus	European Hedgehog	Rabbits/Hares	XP_016043235.1 [50]	93	100	96
Ochotona princeps	American Pika	Insectivoires	XP_004589491.1 [51]	92	100	97

The most distantly detectable organisms with homology in the gene are bony fishes including salmon and the common carp, but similarity to the human protein sequence is markedly less than that of mammals. No traces of the gene can be seen in intermediates between mammals and bony fishes such as reptiles or amphibians:

Organism	Common Name	Classification	Accession Number	Percent Identity	Query Cover	Percent Similarity
Homo sapiens	Humans	Primate	NP_115663.2 [5]	100	100	100
Cyprinus carpio	Common Carp	Bony Fishes	XP_018946777 [52]	30	41	34
Esox lucius	Northern Pike	Bony Fishes	XP_019899574.1 [53]	31	55	31
Nothobranchius furzeri	Black Rockcod	Bony Fishes	XP_010767110 [54]	37	35	39