Cryo-EM Structure of Human TLR4/MD-2/DLAM5 Complex

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 ^[1–12]. At the plasma membrane, cooperates with LY96 to mediate the innate immune response to bacterial lipopolysaccharide (LPS) ^[9]. Also involved in LPS-independent inflammatory responses triggered by free fatty acids, such as palmitate, and Ni(2+) ^[7].

Mechanistically, acts via MYD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response ^{[1, 13, 9, 14, 15]}. 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 ^[16]. In addition to the secretion of pro-inflammatory cytokines, initiates the activation of NLRP3 inflammasome and formation of a positive feedback loop between autophagy and NF-kappa-B signaling cascade ^[17].

In complex with TLR6, promotes inflammation in monocytes/macrophages by associating with TLR6 and the receptor CD86 ^[8]. 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 ^[8]. 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 ^{[18, 8]}.

Required for the migration-promoting effects of ZG16B/PAUF on pancreatic cancer cells ^[19]. Acts as an activator of necroptosis, a programmed cell death process, in macrophages (By similarity). In response to LPS, recruits the adapter TRIF/TICAM1, which binds and activates RIPK3 kinase, leading to phosphorylation and activation of MLKL, triggering execution of programmed necrosis via disruption of the plasma membrane (By similarity).

TLR4-mediated necroptosis is independent of TNF-mediated signaling (By similarity)

Binds bacterial lipopolysaccharide (LPS) ^{[1, 2]}. Cooperates with TLR4 in the innate immune response to bacterial lipopolysaccharide (LPS), and with TLR2 in the response to cell wall components from Gram-positive and Gram-negative bacteria ^{[3, 4]}. Enhances TLR4-dependent activation of NF-kappa-B ^[5].

Cells expressing both LY96 and TLR4, but not TLR4 alone, respond to LPS ^[5]