The hepatic galactosyl receptor system: Two different ligand dissociation pathways are mediated by distinct receptor populations

Weigel, Paul H.; Clarke, Benjamin L.; Oka, Janet A.

doi:10.1016/0006-291x(86)91055-7

Cited by 25 publications

(19 citation statements)

References 17 publications

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“…A residual rate of asialoglycoprotein catabolism in the presence of monensin has also been observed in several other studies (Grinde, 1983;Berg et al, 1983;Chang and Kullberg, 1984). This result, although not compelling, is consistent with the existence of two ligand-processing pathways for the Gal receptor system (Weigel, 1987;Weigel et al, 1986).…”

Section: Resultssupporting

confidence: 85%

“…The same result was obtained with cells incubated for 1 h with 50 pM monensin before the addition of acridine orange, We conclude that, in the presence of the ionophore, hepatocytes do not regain their normal ability to reacidify intracellular compartments. We have characterized two functionally distinct subpopulations of Gal receptors in isolated hepatocytes and have proposed that this system actually processes ligand by two separate and parallel pathways (Weigel et al, 1986). Freshly isolated cells prepared by collagenase perfusion and purified as described in Methods express only the state 1 population of receptors.…”

Section: Time (Minutes)mentioning

confidence: 99%

“…Some of the evidence for this conclusion and a model to describe this system have recently been summarized (Weigel et al, 1986;Weigel, 1987). We refer to these two receptor subpopulations and their respective pathways as state 1 and state 2.…”

mentioning

confidence: 97%

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Monensin inhibits ligand dissociation only transiently and partially and distinguishes two galactosyl receptor pathways in isolated rat hepatocytes

Oka¹,

Weigel²

1987

Journal Cellular Physiology

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Monensin has been shown to inhibit the dissociation of internalized asialoorosomucoid (ASOR) from galactosyl (Gal) receptors in hepatocytes (Harford et al., J. Cell. Biol., 96:1824, 1983). Examination of the long-term kinetics of dissociation of a single round of surface-bound 125I-ASOR in the presence of monensin revealed, however, that dissociation resumed after a lag of 30-40 min. Dissociation proceeded slowly with apparent first order kinetics (k = 0.006-0.022 min-1) and reached a plateau after 4 h, both in freshly isolated cells in suspension and in cells cultured for 24 h. Only a portion of the ligand bound to surface Gal receptors was capable of dissociating. The degree of dissociation was correlated with the expression of a subpopulation of receptors we have recently designated as state 1 Gal receptors (Weigel et al., Biochem. Biophys. Res. Commun. 140:43, 1986). The recovery and dissociation of a portion of 125I-ASOR-receptor complexes after the lag period is not due to a depletion of monensin, since a second addition of the drug has no affect once dissociation resumes. Furthermore, as assessed by the accumulation of the fluorescent dye acridine orange, cells have not recovered the ability to acidify intracellular compartments during the time that dissociation occurs. The results support a model for the hepatic Gal receptor system, in which there are two functionally different receptor populations, recycling pathways, and ligand processing pathways. Monensin blocks dissociation of 125I-ASOR from receptors in the major pathway completely. In the minor pathway dissociation proceeds to completion only after a lag. In this minor pathway monensin appears to temporarily delay a maturation or translocation process that must occur prior to dissociation. We conclude that the observed dissociation in the presence of monensin cannot be mediated by low pH, or by pH or pNa gradients.

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Section: Resultssupporting

confidence: 85%

Section: Time (Minutes)mentioning

confidence: 99%

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Monensin inhibits ligand dissociation only transiently and partially and distinguishes two galactosyl receptor pathways in isolated rat hepatocytes

Oka¹,

Weigel²

1987

Journal Cellular Physiology

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“…Alternatively, the internalization of sNS1 by potential target cells might be modulated by the tissue-specific expression of cellular factors that remain to be identified. From several points of view, the biodistribution and clearance of reporter proteins or protein complexes circulating in the blood are highly variable and depend on the nature of the target cells, the mode of entry, and resistance to degradation rather than the actual size of the proteins and do not necessarily involve hepatocytes (6,22,28,54,60).…”

Section: Vol 79 2005mentioning

confidence: 99%

The Secreted Form of Dengue Virus Nonstructural Protein NS1 Is Endocytosed by Hepatocytes and Accumulates in Late Endosomes: Implications for Viral Infectivity

Alcon-LePoder

Drouet

Roux

et al. 2005

J Virol

110

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The flavivirus nonstructural protein NS1 is expressed as three discrete species in infected mammalian cells: an intracellular, membrane-associated form essential for viral replication, a cell surface-associated form that may be involved in signal transduction, and a secreted form (sNS1), the biological properties of which remain elusive. To determine the distribution of the dengue virus (DEN) sNS1 protein in vivo, we have analyzed by immunohistological means the tissue tropism of purified DEN sNS1 injected intravenously into adult mice. The sNS1 protein was found predominantly associated with the liver, where hepatocytes appeared to represent a major target cell. We further showed that sNS1 could be efficiently endocytosed by human Huh7 and HepG2 hepatocytes in vitro. After its internalization, the protein was detected intracellularly for at least 48 h without being substantially degraded. Colocalization studies of sNS1 with markers of the endolysosomal compartments revealed that the protein was specifically targeted to lysobisphosphatidic acid-rich structures reminiscent of late endosomes, as confirmed by electron microscopy. Intracellular accumulation of sNS1 in Huh7 cells enhanced the fluid phase uptake of rhodamine-labeled dextran. Furthermore, preincubation of Huh7 cells with sNS1 increased dengue virus production after infection with the homologous strain of DEN-1 virus. Our results demonstrate that the accumulation of DEN sNS1 in the late endosomal compartment of hepatocytes potentializes subsequent dengue virus infection in vitro, raising the possibility that sNS1 may contribute to viral propagation in vivo.

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“…Dissociated ligands are delivered to lysosomes for degradation, and receptors are recycled back to the cell surface. Previous studies by us (2-4) and others (5)(6)(7) have demonstrated that ligands are endocytosed and intracellularly processed via two distinct pathways by two functionally distinct receptor populations, designated State 1 ASGP-Rs and State 2 ASGP-Rs (4).…”

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confidence: 99%

Fatty Acylation of the Rat and Human Asialoglycoprotein Receptors

Zeng

Weigel

1996

Journal of Biological Chemistry

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Functional rat or human asialoglycoprotein receptors (ASGP-Rs) are hetero-oligomeric integral membrane glycoproteins. Rat ASGP-R contains three subunits, designated rat hepatic lectins (RHL) 1, 2, and 3; human ASGP-R contains two subunits, HHL1 and HHL2. The hepatic asialoglycoprotein receptor (ASGP-R) 1 has been a good model system for studying receptor-mediated endocytosis (1, 2). ASGP-Rs mediate the endocytosis of plasma glycoconjugates containing terminal galactosyl or N-acetylgalactosaminyl residues through a coated pit pathway. The receptorligand complexes are rapidly endocytosed and dissociated within endosomes. Dissociated ligands are delivered to lysosomes for degradation, and receptors are recycled back to the cell surface. Previous studies by us (2-4) and others (5-7) have demonstrated that ligands are endocytosed and intracellularly processed via two distinct pathways by two functionally distinct receptor populations, designated State 1 ASGP-Rs and State 2 ASGP-Rs (4).That State 2 ASGP-Rs undergo a transient inactivation/ reactivation cycle during receptor recycling indicates that regulation of receptor activity may be an important, and perhaps general, characteristic during endocytosis and receptor recycling (8 -10). In permeable rat hepatocytes, this State 2 receptor population is inactivated by ATP in the absence of cytosol (9), and the ATP-inactivated receptors can be quantitatively reactivated by the simple addition of palmitoyl-CoA (10, 11). Recently, we showed in both rat hepatocytes (12, 13) and human hepatoma cells (14) that State 2 ASGP-Rs are palmitoylated and that depalmitoylation with hydroxylamine causes inactivation of this same receptor population. We proposed that a dynamic fatty acylation/deacylation cycle may be the molecular basis for the State 2 ASGP-R inactivation/reactivation cycle in vivo (12,14).Physiologically, this receptor inactivation/reactivation cycle during endocytosis could explain why endocytosis mediated by a variety of recycling receptors is so efficient (2). Receptor inactivation shortly after internalization would eliminate the possibility of dissociated ligand rebinding to receptors during the segregation step in which the two are being separated and directed to different intracellular pathways. Transient receptor inactivation also ensures that the efficiency of the segregation process would not decrease as the extracellular ligand concentration (and presumably the need for efficient clearance) increased.The rat ASGP-R is an integral transmembrane glycoprotein composed of three polypeptide subunits, designated rat hepatic lectin (RHL) 1, 2, and 3, with molecular masses of 41.5, 49, and 54 kDa, respectively. The three subunits are the products of two different genes (15). RHL2 and RHL3 contain the same polypeptide backbone but differ in the type and extent of posttranslational carbohydrate modification (16). The human ASGP-R contains two subunits designated HHL1 and HHL2, also encoded by two genes (1). Each RHL and HHL subunit contains a single conserved Cys in i...

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The hepatic galactosyl receptor system: Two different ligand dissociation pathways are mediated by distinct receptor populations

Cited by 25 publications

References 17 publications

Monensin inhibits ligand dissociation only transiently and partially and distinguishes two galactosyl receptor pathways in isolated rat hepatocytes

Monensin inhibits ligand dissociation only transiently and partially and distinguishes two galactosyl receptor pathways in isolated rat hepatocytes

The Secreted Form of Dengue Virus Nonstructural Protein NS1 Is Endocytosed by Hepatocytes and Accumulates in Late Endosomes: Implications for Viral Infectivity

Fatty Acylation of the Rat and Human Asialoglycoprotein Receptors

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