Alternative titles; symbols
HGNC Approved Gene Symbol: LBP
Cytogenetic location: 20q11.23 Genomic coordinates (GRCh38): 20:38,346,482-38,377,013 (from NCBI)
Lipopolysaccharide-binding protein is an acute-phase reactant produced during gram-negative bacterial infections. Higher eukaryotes have evolved several mechanisms for protecting against such infections. Gram-negative bacteria express lipopolysaccharide (LPS; endotoxin) on their outer cell wall, and mammals respond rapidly to the presence of LPS in serum. LBP and another acute-phase reactant, bactericidal permeability-increasing protein (BPI; 109195), bind LPS with high affinity. LBP is made in the liver during the acute phase of infections and is thought to function as a carrier for LPS and to help control LPS-dependent monocyte responses. See CD14 (158120) for information on the receptor for the lipopolysaccharide binding protein/lipopolysaccharide complex.
By screening a human liver cDNA library with an oligonucleotide derived from the rabbit LBP protein sequence, Schumann et al. (1990) isolated cDNAs encoding LBP. The predicted human LBP protein consists of a 25-amino acid signal sequence followed by a 452-amino acid mature protein containing 4 cysteine residues and 5 potential glycosylation sites. Human LBP shares 69% amino acid identity with rabbit LBP, 44% identity with human BPI, and 23% identity with human CETP (118470). In rabbits, Schumann et al. (1990) found that LBP functions as a carrier protein for LPS in plasma and controls LPS-dependent monocytic responses.
Hubacek et al. (1997) found that the LBP gene spans approximately 28.5 kb of DNA and contains 14 exons. Comparison of the genomic structures of LBP, BPI, PLTP (172425), and CETP, which constitute a family of functionally related proteins, revealed a remarkable conservation of exon/intron junctions and exon size.
LPS interacts with LBP and CD14 to present LPS to TLR4 (603030), which activates inflammatory gene expression through NF-kappa-B (see 164011) and MAPK signaling. Bochkov et al. (2002) demonstrated that oxidized phospholipids inhibit LPS-induced but not TNF-alpha (191160)-induced or interleukin-1-beta (147720)-induced NF-kappa-B-mediated upregulation of inflammatory genes by blocking the interaction of LPS with LBP and CD14. Moreover, in LPS-injected mice, oxidized phospholipids inhibited inflammation and protected mice from lethal endotoxin shock. Thus, in severe gram-negative bacterial infection, endogenously formed oxidized phospholipids may function as a negative feedback to blunt innate immune responses. Furthermore, Bochkov et al. (2002) identified chemical structures capable of inhibiting the effects of endotoxins such as LPS that could be used for the development of new drugs for treatment of sepsis.
Weber et al. (2003) found that LBP was present in the cerebrospinal fluid of patients with pneumococcal meningitis. Injection of living pneumococci or pneumococcal cell wall (PCW) into spinal canals of Lbp +/- mice resulted in leukocyte influx and severe meningitis. In contrast, injection into Lbp -/- mice produced no meningeal inflammation. Lbp enhanced PCW-induced signaling and Tnf release in rodent cell lines, and Lbp bound to PCW multimers independently of the phosphorylcholine and teichoic acid components of PCW. Experiments using human LBP suggested that the binding site for PCW may overlap with that for LPS. Weber et al. (2003) concluded that LBP is also involved in gram-positive infections.
Crystal Structure
Eckert et al. (2013) reported the crystal structure of murine Lbp at 2.9-angstrom resolution. Several structural differences were observed between Lbp and the related bactericidal/permeability-increasing protein (BPI; 109195), and the Lbp C-terminal domain contained a negatively charged groove and a hydrophobic 'phenylalanine core.'
Eckert et al. (2013) identified a single-nucleotide polymorphism (SNP) close to the phenylalanine core of the LBP gene that potentially generates a proteinase cleavage site and that may influence inflammatory response (rs2232613; 151990.0001).
In addition to the functional relationship and extensive structural similarity between the LBP and BPI proteins, the LBP and BPI genes were found by Southern blot analysis of human/mouse somatic cell hybrids and by in situ hybridization to map to the same region of the genome: 20q11.23-q.12 (Gray et al., 1993).
By using mice deficient in LBP through gene knockout experiments, Jack et al. (1997) investigated how LBP functions in vivo. To their surprise, they found that LBP is not required in vivo for the clearance of LPS from the circulation, but is essential for the rapid induction of an inflammatory response by small amounts of LPS or gram-negative bacteria and for survival of an intraperitoneal Salmonella infection.
This variant is classified as a variant of unknown significance because its contribution to cytokine induction following bacterial stimulation has not been confirmed.
Eckert et al. (2013) identified a frequent human LBP SNP, rs2232613 (allelic frequency 0.08), affecting the C-terminal phenylalanine core and potentially generating a proteinase cleavage site. The SNP rs2232613 represents a C-to-T transition at nucleotide 998 of LBP that results in a pro333-to-leu (P333L) amino acid substitution. The P333L mutation occurs at a highly conserved amino acid, and the change from proline to leucine leads to the generation of a potential cleavage site for the proteases chymotrypsin (see 118890), pepsin (see 169700), and proteinase K. Using ELISA, Eckert et al. (2013) showed that the mutant protein had a reduced binding capacity for LPS and lipopeptides in vitro. Eckert et al. (2013) analyzed LBP serum concentrations using a commercial ELISA assay in a cohort of over 3,000 German children and detected several individuals with apparently low serum concentrations. These children were homozygous for the rs2232613 polymorphism. In a cross-sectional population study of 3,061 German children (Schedel et al., 2008), 14 homozygotes and 454 heterozygotes for the T allele of the polymorphism were identified, for an allele frequency of 0.08. Whereas 0.46% homozygous children were identified, no homozygous individuals were found among the 627 healthy adults tested. Eckert et al. (2013) found that sera from P333L carriers contained cleaved LBP, and functional models showed that P333L LBP did not bind lipopolysaccharide (LPS) or induce cytokines in vitro. Furthermore, individuals with the P333L mutation had lower cytokine concentrations in serum after experimental LPS application. Eckert et al. (2013) genotyped 157 patients with ventilator-associated pneumonia caused by gram-negative bacteria and found 10 heterozygotes and 2 homozygotes for the T allele of rs2232613, leading to an allele frequency of 0.07. Heterozygotes had significantly lower cytokine concentrations (6.2 +/- 1.76 pg/ml) compared to wildtype individuals (18.4 +/- 4.9 pg/ml, p = 0.014). Homozygotes had the lowest TNF (191160) concentrations (3.93 +/- 1.76 pg/ml). Eckert et al. (2013) also analyzed 424 patients with a prolonged intensive care stay. They identified 57 heterozygotes and 4 homozygotes, for an allele frequency of 0.08. All 4 homozygotes developed infectious complications, and 3 became septic. However, these numbers were too small to allow for statistical analysis. Among the heterozygous individuals, no change in susceptibility for infectious diseases could be detected. Eckert et al. (2013) concluded that their retrospective clinical analysis proposed that individuals carrying this mutation are at risk for fatal sepsis and pneumonia, although these results must be confirmed in larger trials. The exact role of this mutation in vivo could not be completely elucidated because LBP might also play a role in inflammatory diseases affecting overall clinical outcome.
Bochkov, V. N., Kadl, A., Huber, J., Gruber, F., Binder, B. R., Leitinger, N. Protective role of phospholipid oxidation products in endotoxin-induced tissue damage. Nature 419: 77-81, 2002. [PubMed: 12214235] [Full Text: https://doi.org/10.1038/nature01023]
Eckert, J. K., Kim, Y. J., Kim, J. I., Gurtler, K., Oh, D.-Y., Sur, S., Lundvall, L., Hamann, L., van der Ploeg, A., Pickkers, P., Giamarellos-Bourboulis, E., Kubarenko, A. V., Weber, A. N., Kabesch, M., Kumpf, O., An, H.-J., Lee, J.-O., Schumann, R. R. The crystal structure of lipopolysaccharide binding protein reveals the location of a frequent mutation that impairs innate immunity. Immunity 39: 647-660, 2013. [PubMed: 24120359] [Full Text: https://doi.org/10.1016/j.immuni.2013.09.005]
Gray, P. W., Corcorran, A. E., Eddy, R. L., Jr., Byers, M. G., Shows, T. B. The genes for the lipopolysaccharide binding protein (LBP) and the bactericidal permeability increasing protein (BPI) are encoded in the same region of human chromosome 20. Genomics 15: 188-190, 1993. [PubMed: 8432532] [Full Text: https://doi.org/10.1006/geno.1993.1030]
Hubacek, J. A., Buchler, C., Aslanidis, C., Schmitz, G. The genomic organization of the genes for human lipopolysaccharide binding protein (LBP) and bactericidal permeability increasing protein (BPI) is highly conserved. Biochem. Biophys. Res. Commun. 236: 427-430, 1997. [PubMed: 9240454] [Full Text: https://doi.org/10.1006/bbrc.1997.6970]
Jack, R. S., Fan, X., Bernheiden, M., Rune, G., Ehlers, M., Webert, A., Kirsch, G., Mentel, R., Furll, B., Freudenberg, M., Schmitz, G., Stelter, F., Schutt, C. Lipopolysaccharide-binding protein is required to combat a murine gram-negative bacterial infection. Nature 389: 742-744, 1997. [PubMed: 9338787] [Full Text: https://doi.org/10.1038/39622]
Schedel, M., Pinto, L. A., Schaub, B., Rosenstiel, P., Cherkasov, D., Cameron, L., Klopp, N., Illig, T., Vogelberg, C., Weiland, S. K., von Mutius, E., Lohoff, M., Kabesch, M. IRF-1 gene variations influence IgE regulation and atopy. Am. J. Resp. Crit. Care Med. 177: 613-621, 2008. [PubMed: 18079498] [Full Text: https://doi.org/10.1164/rccm.200703-373OC]
Schumann, R. R., Leong, S. R., Flaggs, G. W., Gray, P. W., Wright, S. D., Mathison, J. C., Tobias, P. S., Ulevitch, R. J. Structure and function of lipopolysaccharide binding protein. Science 249: 1429-1431, 1990. [PubMed: 2402637] [Full Text: https://doi.org/10.1126/science.2402637]
Weber, J. R., Freyer, D., Alexander, C., Schroder, N. W. J., Reiss, A., Kuster, C., Pfeil, D., Tuomanen, E. I., Schumann, R. R. Recognition of pneumococcal peptidoglycan: an expanded, pivotal role for LPS binding protein. Immunity 19: 269-279, 2003. [PubMed: 12932360] [Full Text: https://doi.org/10.1016/s1074-7613(03)00205-x]