TLR7

Toll-like receptor 7, also known as TLR7, is a protein that in humans is encoded by the TLR7 gene. Orthologs are found in mammals and birds.[5] It is a member of the toll-like receptor (TLR) family and detects single stranded RNA.

TLR7
Identifiers
Aliases	TLR7, TLR7-like, toll like receptor 7
External IDs	OMIM: 300365 MGI: 2176882 HomoloGene: 75060 GeneCards: TLR7
Gene location (Human) Chr. X chromosome (human)[1] Band Xp22.2 Start 12,867,072 bp[1] End 12,890,361 bp[1]
Gene location (Mouse) Chr. X chromosome (mouse)[2] Band X|X F5 Start 167,304,929 bp[2] End 167,330,558 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • transmembrane signaling receptor activity • double-stranded RNA binding • drug binding • siRNA binding • single-stranded RNA binding • GO:0008329 pattern recognition receptor activity Cellular component • integral component of membrane • Golgi membrane • cytoplasmic vesicle • early phagosome • endosome • receptor complex • phagocytic vesicle • membrane • lysosome • endoplasmic reticulum • cell membrane • endolysosome membrane • cytoplasm • endosome membrane • endoplasmic reticulum membrane Biological process • I-kappaB phosphorylation • immune system process • positive regulation of inflammatory response • toll-like receptor 9 signaling pathway • positive regulation of interleukin-8 production • toll-like receptor signaling pathway • regulation of protein phosphorylation • defense response to virus • cellular response to mechanical stimulus • microglial cell activation • positive regulation of interleukin-6 production • MyD88-dependent toll-like receptor signaling pathway • signal transduction • positive regulation of chemokine production • immune response • toll-like receptor 7 signaling pathway • innate immune system • inflammatory response • positive regulation of NIK/NF-kappaB signaling • I-kappaB kinase/NF-kappaB signaling Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	51284	170743
Ensembl	ENSG00000196664	ENSMUSG00000044583
UniProt	Q9NYK1	P58681
RefSeq (mRNA)	NM_016562	NM_133211 NM_001290755 NM_001290756 NM_001290757 NM_001290758
RefSeq (protein)	NP_057646	NP_001277684 NP_001277685 NP_001277686 NP_001277687 NP_573474
Location (UCSC)	Chr X: 12.87 – 12.89 Mb	Chr X: 167.3 – 167.33 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

The TLR family plays an important role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This gene is predominantly expressed in lung, placenta, and spleen, and lies in close proximity to another family member, TLR8, on the human X chromosome.[6]

TLR7 recognizes single-stranded RNA in endosomes, which is a common feature of viral genomes which are internalised by macrophages and dendritic cells. TLR7 recognizes single-stranded RNA of viruses such as HIV and HCV.[7][8] TLR7 can recognize GU-rich single-stranded RNA.[7] However, the presence of GU-rich sequences in the single-stranded RNA is not sufficient to stimulate TLR7.[8]

Clinical significance

TLR7 has been shown to play a significant role in the pathogenesis of autoimmune disorders such as lupus as well as in the regulation of antiviral immunity. Although not yet fully elucidated, using an unbiased genome-scale screen with short hairpin RNA (shRNA), it has been demonstrated that the receptor TREML4 acts as an essential positive regulator of TLR7 signaling. In TREML4 -/- mice macrophages that are hyporesponsive to TLR7 agonists, macrophages fail to produce type I interferons due to impaired phosphorylation of the transcription factor STAT1 by the mitogen-activated protein kinase p38 and decreased recruitment of the adaptor MYD88 to TLR7. TREML4 deficiency reduced the production of inflammatory cytokines and autoantibodies in MRL/lpr mice, suggesting that TLR7 is a vital component of antiviral immunity and a predecessor factor in the pathogenesis of rheumatic diseases such as systemic lupus erythematosus (SLE).[9] A TLR7 agonist, imiquimod (Aldara),[10] has been approved for topical use in treating warts caused by papillomavirus and for actinic keratosis.[11]

Due to their ability to induce robust production of anti-cancer cytokines such as interleukin-12, TLR7 agonists have been investigated for cancer immunotherapy. Recent examples include TMX-202 delivery via liposomal formulation,[12] as well as the delivery of resiquimod via nanoparticles formed from beta-cyclodextrin.[13]

In July 2020, it was discovered that a deficient TLR7 gene caused several young patients to become seriously ill after being infected by SARS-CoV-2.[14] This suggests that TLR7 plays a key role in triggering the immune response for patients of COVID-19. For more details on the biological mechanism and pathway, see "Type I Interferon Induction and Signaling During SARS-CoV-2 Infection" on WikiPathways.

References

1. GRCh38: Ensembl release 89: ENSG00000196664 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000044583 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Du X, Poltorak A, Wei Y, Beutler B (September 2000). "Three novel mammalian toll-like receptors: gene structure, expression, and evolution". European Cytokine Network. 11 (3): 362–71. PMID 11022119.
6. "Entrez Gene: TLR7 toll-like receptor 7".
7. Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, Lipford G, Wagner H, Bauer S (March 2004). "Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8". Science. 303 (5663): 1526–9. doi:10.1126/science.1093620. PMID 14976262.
8. Zhang Y, El-Far M, Dupuy FP, Abdel-Hakeem MS, He Z, Procopio FA, Shi Y, Haddad EK, Ancuta P, Sekaly RP, Said EA (July 2016). "HCV RNA Activates APCs via TLR7/TLR8 While Virus Selectively Stimulates Macrophages Without Inducing Antiviral Responses". Scientific Reports. 6: 29447. doi:10.1038/srep29447. PMC 4935957. PMID 27385120.
9. Ramirez-Ortiz ZG, Prasad A, Griffith JW, Pendergraft WF, Cowley GS, Root DE, Tai M, Luster AD, El Khoury J, Hacohen N, Means TK (May 2015). "The receptor TREML4 amplifies TLR7-mediated signaling during antiviral responses and autoimmunity". Nature Immunology. 16 (5): 495–504. doi:10.1038/ni.3143. PMC 4406861. PMID 25848864.
10. Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H, Hoshino K, Horiuchi T, Tomizawa H, Takeda K, Akira S (February 2002). "Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway". Nature Immunology. 3 (2): 196–200. doi:10.1038/ni758. PMID 11812998.
11. Vender RB, Goldberg O (January 2005). "Innovative uses of imiquimod". Journal of Drugs in Dermatology. 4 (1): 58–63. PMID 15696986.
12. Klauber TC, Laursen JM, Zucker D, Brix S, Jensen SS, Andresen TL (April 2017). "Delivery of TLR7 agonist to monocytes and dendritic cells by DCIR targeted liposomes induces robust production of anti-cancer cytokines". Acta Biomaterialia. 53: 367–377. doi:10.1016/j.actbio.2017.01.072. PMID 28153581.
13. Rodell CB, Arlauckas SP, Cuccarese MF, Garris CS, Li R, Ahmed MS, Kohler RH, Pittet MJ, Weissleder R (2018-05-21). "TLR7/8-agonist-loaded nanoparticles promote the polarization of tumour-associated macrophages to enhance cancer immunotherapy". Nature Biomedical Engineering. 2 (8): 578–588. doi:10.1038/s41551-018-0236-8. PMID 31015631.
14. van der Made, Caspar I.; Simons, Annet; Schuurs-Hoeijmakers, Janneke; van den Heuvel, Guus; Mantere, Tuomo; Kersten, Simone; van Deuren, Rosanne C.; Steehouwer, Marloes; van Reijmersdal, Simon V.; Jaeger, Martin; Hofste, Tom (2020-07-24). "Presence of Genetic Variants Among Young Men With Severe COVID-19". JAMA. doi:10.1001/jama.2020.13719. ISSN 0098-7484.

Further reading

• Lien E, Ingalls RR (January 2002). "Toll-like receptors". Critical Care Medicine. 30 (1 Suppl): S1–11. doi:10.1097/00003246-200201001-00001. PMID 11782555.
• Kaisho T, Akira S (February 2002). "Toll-like receptors as adjuvant receptors". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1589 (1): 1–13. doi:10.1016/S0167-4889(01)00182-3. PMID 11909637.

External links

• Toll-Like+Receptor+7 at the US National Library of Medicine Medical Subject Headings (MeSH)