View source for Biology:Toll-like receptor 8

{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox_gene}}
'''Toll-like receptor 8''' is a [[Biology:Protein|protein]] that in humans is encoded by the ''TLR8'' [[Biology:Gene|gene]].<ref name="pmid11022119">{{cite journal | vauthors = Du X, Poltorak A, Wei Y, Beutler B | title = Three novel mammalian toll-like receptors: gene structure, expression, and evolution | journal = European Cytokine Network | volume = 11 | issue = 3 | pages = 362–71 | date = September 2000 | pmid = 11022119 | url = http://www.jle.com/medline.md?issn=1148-5493&vol=11&iss=3&page=362 }}</ref> TLR8 has also been designated as '''CD288''' ([[Biology:Cluster of differentiation|cluster of differentiation]] 288). It is a member of the [[Biology:Toll-like receptor|toll-like receptor]] (TLR) family.

== Function ==

TLR8 seems to function differently in humans and mice.  Until recently, TLR8 was believed to be nonfunctional in mice, but it seems to counteract TLR7 activity<ref name="pmid20811154">{{cite journal | vauthors = Demaria O, Pagni PP, Traub S, de Gassart A, Branzk N, Murphy AJ, Valenzuela DM, Yancopoulos GD, Flavell RA, Alexopoulou L | title = TLR8 deficiency leads to autoimmunity in mice | journal = The Journal of Clinical Investigation | volume = 120 | issue = 10 | pages = 3651–62 | date = October 2010 | pmid = 20811154 | pmc = 2947223 | doi = 10.1172/JCI42081 }}</ref><ref name="pmid22817608">{{cite journal | vauthors = Sarvestani ST, Williams BR, Gantier MP | title = Human Toll-like receptor 8 can be cool too: implications for foreign RNA sensing | journal = Journal of Interferon & Cytokine Research | volume = 32 | issue = 8 | pages = 350–61 | date = August 2012 | pmid = 22817608 | doi = 10.1089/jir.2012.0014 }}</ref>

The TLR family plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from ''[[Biology:Drosophila|Drosophila]]'' to [[Humans|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 [[Biology:Cytokine|cytokine]]s necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This gene is predominantly expressed in lung and peripheral blood leukocytes, and lies in close proximity to another family member, [[Biology:TLR7|TLR7]], on chromosome X.<ref>{{cite web |title=Entrez Gene: TLR8 toll-like receptor 8 |url=https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=51311 }}</ref> Recent research has also shown the expression of TLR8 in hippocampal interneurons, with yet unknown function.<ref>Seizer L, Rahimi S, Santos-Sierra S, Drexel M (2022) Expression of toll like receptor 8 (TLR8) in specific groups of mouse hippocampal interneurons. PLoS ONE 17(5): e0267860. https://doi.org/10.1371/journal.pone.0267860</ref>

TLR8 can recognize GU-rich single-stranded RNA.<ref name=pmid14976262>{{cite journal | vauthors = Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, Lipford G, Wagner H, Bauer S | title = Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8 | journal = Science | volume = 303 | issue = 5663 | pages = 1526–9 | date = March 2004 | pmid = 14976262 | doi = 10.1126/science.1093620 | bibcode = 2004Sci...303.1526H | s2cid = 1680581 | doi-access = free }}</ref> However, the presence of GU-rich sequences in the single-stranded RNA is not sufficient to stimulate TLR8.<ref name=pmid27385120>{{cite journal | vauthors = Zhang Y, El-Far M, Dupuy FP, Abdel-Hakeem MS, He Z, Procopio FA, Shi Y, Haddad EK, Ancuta P, Sekaly RP, Said EA | title = HCV RNA Activates APCs via TLR7/TLR8 While Virus Selectively Stimulates Macrophages Without Inducing Antiviral Responses | journal = Scientific Reports | volume = 6 | pages = 29447 | date = July 2016 | pmid = 27385120 | pmc = 4935957 | doi = 10.1038/srep29447 | bibcode = 2016NatSR...629447Z }}</ref> TLR8 recognizes G-rich [[Chemistry:Oligonucleotide|oligonucleotide]]s.<ref name="pmid16123302">{{cite journal | vauthors = Peng G, Guo Z, Kiniwa Y, Voo KS, Peng W, Fu T, Wang DY, Li Y, Wang HY, Wang RF | title = Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function | journal = Science | volume = 309 | issue = 5739 | pages = 1380–4 | date = August 2005 | pmid = 16123302 | doi = 10.1126/science.1113401 | bibcode = 2005Sci...309.1380P | s2cid = 11952027 }}</ref> TLR8 is activated by ssRNA and forms a dimer complex when uridine released from the degraded ssRNA binds at one active site in between the dimers and a short oligonucleotide binds to another active site on the surface of the TLR8 structure.<ref>{{cite journal | vauthors = Tanji H, Ohto U, Shibata T, Taoka M, Yamauchi Y, Isobe T, Miyake K, Shimizu T | display-authors = 6 | title = Toll-like receptor 8 senses degradation products of single-stranded RNA | journal = Nature Structural & Molecular Biology | volume = 22 | issue = 2 | pages = 109–115 | date = February 2015 | pmid = 25599397 | doi = 10.1038/nsmb.2943 | s2cid = 32208414 }}</ref>

TLR8 is an endosomal receptor that recognizes single stranded RNA (ssRNA), and can recognize ssRNA viruses such as Influenza, Sendai, and Coxsackie B viruses. TLR8 binding to the viral RNA recruits the myeloid differentiation primary response protein 88 (MyD88) and leads to activation of the transcription factor NF-κB and an antiviral response that leads to proinflammatory cytokine synthesis.<ref name="url_invivoGen">{{cite web |url=http://www.invivogen.com/review-tlr7-tlr8 |title=TLR7 and TLR8: Key players in the antiviral response - Innate immunity |work=invivoGen  |date=Fall 2006}}</ref><ref name="Huang_2021">{{cite journal | vauthors = Huang X, Zhang X, Lu M | title = Recent trends in the development of Toll-like receptor 7/8-targeting therapeutics | journal = Expert Opinion on Drug Discovery | volume = 16 | issue = 8 | pages = 869–880 | date = August 2021 | pmid = 33678093 | doi = 10.1080/17460441.2021.1898369 | s2cid = 232141585 }}</ref> TLR8 recognizes single-stranded RNA of viruses such as HIV and HCV.<ref name=pmid14976262/><ref name=pmid27385120/> TLR8 is also involved in the activation of dendritic cells to produce inflammatory factors to help regulate tumor growth, so TLR8 is often used as a target in the research for therapies in treating cancers including ovarian cancer and lymphomas.<ref name="Huang_2021" />

==Clinical significance==
Genetic variants in TLR8 has recently been linked to susceptibility to pulmonary tuberculosis.<ref name="pmid1">{{cite journal | vauthors = Davila S, Hibberd ML, Hari Dass R, Wong HE, Sahiratmadja E, Bonnard C, Alisjahbana B, Szeszko JS, Balabanova Y, Drobniewski F, van Crevel R, van de Vosse E, Nejentsev S, Ottenhoff TH, Seielstad M | title = Genetic association and expression studies indicate a role of toll-like receptor 8 in pulmonary tuberculosis | journal = PLOS Genetics | volume = 4 | issue = 10 | pages = e1000218 | date = October 2008 | pmid = 18927625 | pmc = 2568981 | doi = 10.1371/journal.pgen.1000218 | doi-access = free }}</ref>

===As a drug target===
* TLR8 agonists (e.g. VTX-2337) have undergone clinical trials as immune stimulants in combination therapy for some cancers.<ref>{{cite web | url = http://www.targetedonc.com/conference/sgo-2017/immune-stimulant-no-help-when-added-to-chemotherapy-for-recurrent-ovarian-cancer | title = Immune Stimulant No Help When Added to Chemotherapy for Recurrent Ovarian Cancer. | date = March 2017 | work = Targeted Oncology }}</ref>
* TLR8 antagonists (e.g. CU-CPT9a) may have therapeutic applications against autoimmune disorders.<ref name="pmid30100350">{{cite journal | vauthors = Hu Z, Tanji H, Jiang S, Zhang S, Koo K, Chan J, Sakaniwa K, Ohto U, Candia A, Shimizu T, Yin H | title = Small-Molecule TLR8 Antagonists via Structure-Based Rational Design | journal = Cell Chemical Biology | volume = 25 | issue = 10 | pages = 1286–1291.e3 | date = October 2018 | pmid = 30100350 | pmc = 6195466 | doi = 10.1016/j.chembiol.2018.07.004 }}</ref>

== References ==
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== Further reading ==
{{refbegin | 2}}
* {{cite journal | vauthors = Lien E, Ingalls RR | title = Toll-like receptors | journal = Critical Care Medicine | volume = 30 | issue = 1 Suppl | pages = S1-11 | date = January 2002 | pmid = 11782555 | doi = 10.1097/00003246-200201001-00001 }}
* {{cite journal | vauthors = Kaisho T, Akira S | title = Toll-like receptors as adjuvant receptors | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1589 | issue = 1 | pages = 1–13 | date = February 2002 | pmid = 11909637 | doi = 10.1016/S0167-4889(01)00182-3 | doi-access = free }}
{{refend}}

== External links ==
* {{MeshName|Toll-Like+Receptor+8}}
* [https://www.ebi.ac.uk/pdbe/pdbe-kb/proteins/Q9NR97 PDBe-KB] provides an overview of all the structure information available in the PDB for Human Toll-like receptor 8 (TLR8)

{{Clusters of differentiation}}

[[Category:Toll-like receptors|8]]
[[Category:Clusters of differentiation]]

{{Sourceattribution|Toll-like receptor 8}}