Toll-like receptor 8

Function

Endosomal receptor that plays a key role in innate and adaptive immunity. Controls host immune response against pathogens through recognition of RNA degradation products specific to microorganisms that are initially processed by RNASET2. Recognizes GU-rich single-stranded RNA (GU-rich RNA) derived from SARS-CoV-2, SARS-CoV-1 and HIV-1 viruses. Upon binding to agonists, undergoes dimerization that brings TIR domains from the two molecules into direct contact, leading to the recruitment of TIR-containing downstream adapter MYD88 through homotypic interaction. In turn, the Myddosome signaling complex is formed involving IRAK4, IRAK1, TRAF6, TRAF3 leading to activation of downstream transcription factors NF-kappa-B and IRF7 to induce pro-inflammatory cytokines and interferons, respectively.

Classification

Family (Pfam)

PF13855 LRR_8, PF01582 TIR

InterPro

Cys-rich_flank_reg_C, Leu-rich_rpt, Leu-rich_rpt_typical-subtyp, LRR_dom_sf, TIR_dom, Toll_tir_struct_dom_sf

Functional cluster

Immunoglobulin-Domain Cell Adhesion Proteins

Experimental structures · PDB · 39

• 3W3G X-ray 2.30A
• 3W3J X-ray 2.00A
• 3W3K X-ray 2.30A
• 3W3L X-ray 2.33A
• 3W3M X-ray 2.70A
• 3W3N X-ray 2.10A
• 3WN4 X-ray 1.81A
• 4QBZ X-ray 2.00A
• 4QC0 X-ray 2.10A
• 4R07 X-ray 2.00A
• 4R08 X-ray 2.40A
• 4R09 X-ray 2.62A
• … and 27 more

A predicted model is available from AlphaFold.

Gene Ontology · 30

• GO:0036020 endolysosome membrane
• GO:0005789 endoplasmic reticulum membrane
• GO:0010008 endosome membrane
• GO:0009897 external side of plasma membrane
• GO:0000139 Golgi membrane
• GO:0005886 plasma membrane
• GO:0003677 DNA binding
• GO:0003725 double-stranded RNA binding
• GO:0042802 identical protein binding
• GO:0038187 pattern recognition receptor activity
• GO:0003723 RNA binding
• GO:0038023 signaling receptor activity
• GO:0003727 single-stranded RNA binding
• GO:0007249 canonical NF-kappaB signal transduction
• GO:0071260 cellular response to mechanical stimulus
• GO:0051607 defense response to virus
• GO:0016064 immunoglobulin mediated immune response
• GO:0006954 inflammatory response
• GO:0045087 innate immune response
• GO:0043123 positive regulation of canonical NF-kappaB signal transduction
• GO:0045089 positive regulation of innate immune response
• GO:0032727 positive regulation of interferon-alpha production
• GO:0032728 positive regulation of interferon-beta production
• GO:0032731 positive regulation of interleukin-1 beta production
• GO:0032755 positive regulation of interleukin-6 production
• GO:0032757 positive regulation of interleukin-8 production
• GO:0032729 positive regulation of type II interferon production
• GO:0009615 response to virus
• GO:0034158 toll-like receptor 8 signaling pathway
• GO:0002224 toll-like receptor signaling pathway

Disease associations

• immunodeficiency 98 with autoinflammation, X-linked MONDO:0024777

Drugs targeting this protein · 6

• MOTOLIMOD agonist
• RESIQUIMOD agonist
• TELRATOLIMOD agonist
• SELGANTOLIMOD agonist
• AFIMETORAN inhibitor
• ENPATORAN antagonist

Related proteins · sequence + function similarity

• Toll-like receptor 8 0.98
• Toll-like receptor 7 0.95
• Toll-like receptor 7 0.93
• Toll-like receptor 4 0.87
• Toll-like receptor 2 0.85
• Toll-like receptor 2 0.85
• Toll-like receptor 2 0.85
• Toll-like receptor 2 0.85
• Toll-like receptor 2 0.85
• Toll-like receptor 2 0.85
• Toll-like receptor 2 0.84
• Toll-like receptor 2 0.84

Co-cited proteins · studied together in the literature

• Ribonuclease T2 1 shared papers
• Toll-like receptor 9 5 shared papers
• Toll-like receptor 7 4 shared papers
• Myeloid differentiation primary response protein MyD88 2 shared papers
• TLR adapter interacting with SLC15A4 on the lysosome 1 shared papers
• Toll-like receptor 10 2 shared papers
• Interferon regulatory factor 5 1 shared papers
• Solute carrier family 15 member 4 1 shared papers
• Tyrosine-protein kinase BTK 1 shared papers
• Toll-like receptor 5 2 shared papers
• Toll-like receptor 1 2 shared papers
• Myeloid differentiation primary response protein MyD88 1 shared papers

Literature · 21 cited papers

• TLR8/TLR7 dysregulation due to a novel TLR8 mutation causes severe autoimmune hemolytic anemia and autoinflammation in identical twins. Am. J. Hematol. · 2022
• SARS-CoV-2, SARS-CoV-1, and HIV-1 derived ssRNA sequences activate the NLRP3 inflammasome in human macrophages through a non-classical pathway. IScience · 2021
• Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function. Blood · 2021
• TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7-9. Nature · 2020
• TLR8 Is a Sensor of RNase T2 Degradation Products. Cell · 2019
• Toll-Like Receptor 8 Stability is Regulated by Ring Finger 216 in response to circulating MicroRNAs. Am. J. Respir. Cell Mol. Biol. · 2020
• Small-molecule inhibition of TLR8 through stabilization of its resting state. Nat. Chem. Biol. · 2018
• Autoinhibition and relief mechanism by the proteolytic processing of Toll-like receptor 8. Proc. Natl. Acad. Sci. U.S.A. · 2016
• Toll-like receptor 8 senses degradation products of single-stranded RNA. Nat. Struct. Mol. Biol. · 2015
• Endosomal localization of TLR8 confers distinctive proteolytic processing on human myeloid cells. J. Immunol. · 2014
• Structural reorganization of the Toll-like receptor 8 dimer induced by agonistic ligands. Science · 2013
• The heterogeneous allelic repertoire of human Toll-Like receptor (TLR) genes. PLoS ONE · 2009
• … and 9 more in the literature graph