Disease relevance of Asgr1

• Sendai virus efficiently infects cells via the asialoglycoprotein receptor and requires the presence of cleaved F0 precursor proteins for this alternative route of cell entry [1].
• These results suggest that the mannose-N-acetylglucosamine hepatic lectin recognizes specific sugars on the surface of E. coli and may be centrally involved in the nonimmune clearance of nonfimbriated E. coli from the blood of the infected host [2].
• Hepatitis B virus is known to infect hepatocytes after viremia by asialoglycoprotein receptor mediated uptake [3].
• Toxicity of these two compounds is restricted to hepatocytes and can be blocked by asialoglycoproteins but not the native glycoproteins or asialoagalactoglycoprotein derivatives, indicating that the toxicity of the conjugates is mediated by the hepatic asialoglycoprotein receptor [4].
• Repeated administration of the hepatic lectin blocking agents D-galactose or arabinogalactan completely prevented the settling of metastatic cells of sarcoma L-1 tumor in the liver of Balb/c mice and greatly reduced the colonization process of highly metastatic ESb lymphoma cells of the liver of DBA/2 mice [5].

High impact information on Asgr1

• Conjugation of IgG with galactose, with use of the cyanomethyl derivative, did result in very rapid blood clearance via the hepatic lectin; within 3 minutes clearance was essentially complete [6].
• Two pathways for the degradation of the H2 subunit of the asialoglycoprotein receptor in the endoplasmic reticulum [7].
• Endocytosis of the ASGP receptor H1 is reduced by mutation of tyrosine-5 but still occurs via coated pits [8].
• We have mutated the single tyrosine at position 5 in the cytoplasmic domain of the major subunit H1 of the asialoglycoprotein receptor to alanine [8].
• The asialoglycoprotein receptor clears glycoconjugates terminating with sialic acid alpha 2,6GalNAc [9].

Biological context of Asgr1

• The mammalian asialoglycoprotein receptor (ASGPR) is located on the sinusoidal membrane of hepatocytes where it binds and endocytoses galactose-terminated glycoproteins (asialoglycoproteins) [10].
• Recombinant inbred strain mapping has placed the Amog locus close to genes for zinc finger protein-3 and the asialoglycoprotein receptor in a region of mouse chromosome 11 that is homologous to human 17p [11].
• Hepatic asialoglycoprotein receptor activity of pregnant mice increased from the tenth day of gestation, reaching 3-fold the normal adult level just prior to parturition and returning to normal within 1 week postpartum [12].
• Although both INF7 and INF7-K(GalNAc)(2) were found to increase the transfection efficiency on polyplex-mediated gene transfer to parenchymal liver cells by 30-fold, only INF7-K(GalNAc)(2) appeared to do so in an ASGPr-specific manner [13].
• Impaired receptor-mediated endocytosis by the asialoglycoprotein receptor in ethanol-fed mice: implications for studying the role of this receptor in alcoholic apoptosis [14].

Anatomical context of Asgr1

• PVLA-coated beads bound to and were endocytosed by the whole (MHL-1/-2) ASGP receptor-expressing CHO cells like hepatocytes while PVMA (poly-(N-p-vinylbenzyl-O-beta-D-glucopyranosyl-[1-4]-D-gluconamide) did not [15].
• In summary, we have prepared a nontoxic cell-specific lysosome disruptive element that improves gene delivery to parenchymal liver cells via the ASGPr [13].
• Simple sugars with affinity for the macrophage asialoglycoprotein receptor are adjuvants for the humoral immune response to neuraminidase-treated sheep erythrocytes [16].
• We now have investigated this possible alternative route of infection for SV wild-type (SV-wt) strain Fushimi by using a pair of cell lines which differ only with regard to ASGP-R expression [1].
• Similarly, in NIH 3T3 cells singly transfected with the ASGP-R H2a subunit cDNA, ALLN inhibited degradation of the ASGP-R H2a subunit precursor, as well as the degradation of the 35 kDa proteolytic fragment corresponding to the receptor ectodomain, by 3-6-fold [17].

Associations of Asgr1 with chemical compounds

• Serum concentrations of galactose-terminating glycoproteins are not elevated in these ASGPR-deficient mice [10].
• Thereby, the mouse asialoglycoprotein receptor apparently possesses additional binding pockets that accommodate a fucose residue when presented as Le(x) [18].
• Here too, we synthesized a novel glycolipid, which possesses a highly hydrophobic steroid moiety for stable incorporation into liposomes, and a triantennary GalNAc(3)-terminated cluster glycoside with a high nanomolar affinity (2 nm) for the ASGPr [19].
• In addition, the lysine epsilon-amino groups were covalently bound to galactose (galactosyl-PLSP), a ligand for the asialoglycoprotein receptor on hepatocytes [20].
• Overall, our data suggest the involvement of cysteine proteinases located in the endoplasmic reticulum, as well as in post-Golgi compartments, in degradation of the EPO-R and the ASGP-R H2a subunit [17].

Other interactions of Asgr1

• In the absence of MHL-2, knockout mice express MHL-1 protein at reduced levels [10].
• Using asialoglycoprotein receptor H2a and H2b as models, we determined in pulse-chase experiments that both glycoproteins initially bind to calnexin and ERp57 [21].
• The PC-1 protein therefore has an overall structure and membrane orientation that resembles those of the transferrin receptor, the asialoglycoprotein receptor, and the Ia invariant chain [22].
• These cells also express an asialoglycoprotein receptor, a receptor involved in Tg endocytosis in the thyroid, and a Tg transcript smaller than the 8.3-kb thyroidal form [23].
• An intermediate of 35 kD accumulates transiently during ER degradation of the H2 subunit of the asialoglycoprotein receptor; it is derived by an endoproteolytic cleavage in the exoplasmic domain near the transmembrane region [7].

Analytical, diagnostic and therapeutic context of Asgr1

• Effective hepatocyte transplantation using rat hepatocytes with low asialoglycoprotein receptor expression [24].
• Triantennary oligosaccharides containing terminal Gal or Gal-NAc targeted the liver efficiently whereas biantennary oligosaccharides containing terminal Gal residues and differing only in their core fucosylation avoided recognition by the asialoglycoprotein receptor and were cleared unmetabolized by renal filtration [25].
• This frozen section binding assay was utilized to demonstrate the existence of a bone marrow asialoglycoprotein receptor which was found to be capable of binding to PNAhi lymphocytes or asialoglycoproteins bound to synthetic substrates [26].
• Cre-mediated replacement of the lox-delimited genomic segment at MHL-1 with targeting DNA occurs at a frequency three times that of random DNA integration and is sufficiently robust that correctly targeted ES colonies can be identified by PCR screening without relying on any drug selection procedure [27].
• Prevention of suppression of alloreactive capacity following intravenous injection of neuraminidase-treated allogeneic cells by co-injection of agents competing for asialoglycoprotein receptor [28].

References