Recombinant Human Toll-like receptor 4 (TLR4), partial

Function

Transmembrane receptor that functions as a pattern recognition receptor recognizing pathogen- and damage-associated molecular patterns (PAMPs and DAMPs) to induce innate immune responses via downstream signaling pathways (PubMed:10835634, PubMed:15809303, PubMed:16622205, PubMed:17292937, PubMed:17478729, PubMed:20037584, PubMed:20711192, PubMed:23880187, PubMed:27022195, PubMed:29038465, PubMed:17803912, PubMed:15852007). At the plasma membrane, cooperates with LY96 to mediate the innate immune response to bacterial lipopolysaccharide (LPS) (PubMed:27022195). Also involved in LPS-independent inflammatory responses triggered by free fatty acids, such as palmitate, and Ni(2+) (PubMed:20711192). Mechanistically, acts via MYD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (PubMed:10835634, PubMed:21393102, PubMed:27022195, PubMed:36945827, PubMed:9237759). Alternatively, CD14-mediated TLR4 internalization via endocytosis is associated with the initiation of a MYD88-independent signaling via the TICAM1-TBK1-IRF3 axis leading to type I interferon production (PubMed:14517278). In addition to the secretion of proinflammatory cytokines, initiates the activation of NLRP3 inflammasome and formation of a positive feedback loop between autophagy and NF-kappa-B signaling cascade (PubMed:32894580). In complex with TLR6, promotes inflammation in monocytes/macrophages by associating with TLR6 and the receptor CD86 (PubMed:23880187). Upon ligand binding, such as oxLDL or amyloid-beta 42, the TLR4:TLR6 complex is internalized and triggers inflammatory response, leading to NF-kappa-B-dependent production of CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 cytokine, via TICAM1 signaling pathway (PubMed:23880187). In myeloid dendritic cells, vesicular stomatitis virus glycoprotein G but not LPS promotes the activation of IRF7, leading to type I IFN production in a CD14-dependent manner (PubMed:15265881, PubMed:23880187). Required for the migration-promoting effects of ZG16B/PAUF on pancreatic cancer cells

Subcellular Location

Cell membrane (Single-pass type I membrane protein); Early endosome; Cell projection, ruffle

Tissue Specificity

Highly expressed in placenta, spleen and peripheral blood leukocytes (PubMed:9237759, PubMed:9435236). Detected in monocytes, macrophages, dendritic cells and several types of T-cells (PubMed:27022195, PubMed:9237759). Expressed in pancreatic cancer cells but not in normal pancreatic cells (at protein level) (PubMed:36232715)

Subunit

(Microbial infection) Interacts with ebolavirus protein GP; this interaction leads to the production of proinflammatory cytokines and suppressor of cytokine signaling 1/SOCS1

• Medzhitov R. et al. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. — Nature (1997)
• Rock F.L. et al. A family of human receptors structurally related to Drosophila Toll. — Proc. Natl. Acad. Sci. U.S.A. (1998)
• Smirnova I. et al. Phylogenetic variation and polymorphism at the Toll-like receptor 4 locus (TLR4). — Genome Biol. (2000)
• Arbour N.C. et al. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. — Nat. Genet. (2000)
• Nakajima T. et al. Natural selection in the TLR-related genes in the course of primate evolution. — Immunogenetics (2008)
• Georgel P. et al. The heterogeneous allelic repertoire of human Toll-Like receptor (TLR) genes. — PLoS ONE (2009)
• Ota T. et al. Complete sequencing and characterization of 21,243 full-length human cDNAs. — Nat. Genet. (2004)
• Humphray S.J. et al. DNA sequence and analysis of human chromosome 9. — Nature (2004)