Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Toll family of receptors senses microbial invasion and activates defense responses. Toll-like receptor 4 (TLR4) is a member of the Toll family that senses lipopolysaccharide (LPS), a principal membrane component from Gram-negative bacteria. LPS is known as an endotoxin that strongly activates immune cells such as macrophages and dendritic cells. LPS recognition by TLR4 requires an additional accessory molecule, MD-2. MD-2 is associated with the extracellular portion of TLR4, directly binds to LPS, and regulates subsequent LPS-induced TLR4 clustering. LPS recognition occurs on the cell surface. The subcellular distribution of TLR was shown to influence TLR responses. An endoplasmic reticulum (ER) chaperone, glycoprotein 96, is required for the stability of TLR4 and the formation of a TLR4/MD-2 complex in ER. MD-2 facilitates TLR4 glycosylation and its trafficking to the cell surface. Recently, another molecule, a protein associated with Toll-like receptor 4 (PRAT4A), was shown to play a critical role in cell surface expression of TLR4. These molecules control LPS responsiveness by regulating the subcellular distribution of TLR4.
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PMID:Mechanism regulating cell surface expression and activation of Toll-like receptor 4. 1730 55

Immune cells express multiple Toll-like receptors (TLRs) that are concomitantly activated by a variety of pathogen products. Although there is presumably a need to coordinate the expression and function of TLRs in individual cells, little is known about the mechanisms governing this process. We show that a protein associated with TLR4 (PRAT4A) is required for multiple TLR responses. PRAT4A resides in the endoplasmic reticulum, and PRAT4A knockdown inhibited trafficking of TLR1 and TLR4 to the cell surface and ligand-induced trafficking of TLR9 to lysosomes. Other cell-surface molecules were expressed normally on immunocytes from PRAT4A-/- mice. There was impaired cytokine production to TLR ligands, except to the TLR3 ligand poly(I:C), and to whole bacteria. Activation of antigen-specific T helper type 1 responses were also defective. Moreover, PRAT4A-/- bone marrow chimeric mice were resistant to lipopolysaccharide-induced sepsis. These results suggest that PRAT4A regulates the subcellular distribution and response of multiple TLRs and is required for both innate and adaptive immune responses.
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PMID:A protein associated with Toll-like receptor (TLR) 4 (PRAT4A) is required for TLR-dependent immune responses. 1799 91

TLR4/MD-2 plays an important role in the inflammatory responses against lipopolysaccharide (LPS), a principal membrane component in Gram-negative bacteria. LPS recognition by TLR4/MD-2 is followed by the homotypic interaction of TLR4 (TLR4 dimerization) on the cell surface, leading to the activation of the downstream signaling pathways. The activated TLR4 is transported from plasma membrane to lysosomes, where TLR4 is degraded as a mechanism terminating LPS responses. TLR4 endocytosis is dependent on clathrin-coated vesicles. On the other hand, chaperones play an important role in TLR4 trafficking from endoplasmic reticulum (ER) to cell surface, where TLR4 recognizes LPS and activates. Chaperone gp96 and newly identified chaperone PRAT4A differentially regulate TLR4 translocation to the cell surface. In this review, we discuss TLR4 localization from endoplasmic reticulum to the cell surface and from the cell surface to endosome/lysosome that regulate TLR4 activation.
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PMID:Chaperones and transport proteins regulate TLR4 trafficking and activation. 1925 Jul 1