Genetic deficiency in low density lipoprotein receptor-related protein confers cellular resistance to Pseudomonas exotoxin A

Evidence that this protein is required for uptake and degradation of multiple ligands

Thomas E. Willnow, Joachim Herz

Research output: Contribution to journalArticle

138 Citations (Scopus)

Abstract

The low density lipoprotein receptor-related protein (LRP) is a large multifunctional receptor implicated in the cellular uptake of functionally diverse ligands. Biochemical evidence suggests that LRP is a clearance receptor for apoE-rich remnant lipoproteins, lipoprotein lipase, α2-macroglobulin/protease complexes, plasminogen activator/inhibitor complexes, the active protease tissue-type plasminogen activator and exotoxin A from Pseudomonas aeruginosa. Mice genetically deficient in LRP die early during gestation, underscoring the essential physiological role of this gene in vivo. To study the effect of LRP deficiency at the cellular level, we have used Pseudomonas exotoxin A (PEA) to select murine embryonic fibroblasts that are genetically deficient in LRP. Our results demon-strate that this single gene defect is sufficient to confer resistance to PEA on cultured cells. In addition, embryonic flbroblasts lacking LRP are unable to bind, internalize and degrade methylamine-activated α2-macroglobulin and complexes of urokinase with plasminogen activator inhibitor-1. Furthermore, cellular uptake and degradation of receptor-associated protein, a 39 kDa accessory protein of LRP, is reduced by 90% in the absence of LRP. These results provide genetic evidence for the multifunctional nature of LRP and its crucial role in protease/inhibitor complex metabolism.

Original languageEnglish (US)
Pages (from-to)719-726
Number of pages8
JournalJournal of Cell Science
Volume107
Issue number3
StatePublished - Mar 1994

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LDL-Receptor Related Proteins
Lipoprotein Receptors
LDL Receptors
Ligands
Proteins
Macroglobulins
LDL-Receptor Related Protein-Associated Protein
Peptide Hydrolases
Low Density Lipoprotein Receptor-Related Protein-1
Plasminogen Inactivators
Exotoxins
Protein Deficiency
Inborn Genetic Diseases
Pseudomonas aeruginosa toxA protein
Lipoprotein Lipase
Plasminogen Activator Inhibitor 1
Urokinase-Type Plasminogen Activator
Tissue Plasminogen Activator
Protease Inhibitors
Pseudomonas aeruginosa

Keywords

  • α2-macroglobulin
  • ApoE
  • Homologous recombination
  • Pseudomonas exotoxin A

ASJC Scopus subject areas

  • Cell Biology

Cite this

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title = "Genetic deficiency in low density lipoprotein receptor-related protein confers cellular resistance to Pseudomonas exotoxin A: Evidence that this protein is required for uptake and degradation of multiple ligands",
abstract = "The low density lipoprotein receptor-related protein (LRP) is a large multifunctional receptor implicated in the cellular uptake of functionally diverse ligands. Biochemical evidence suggests that LRP is a clearance receptor for apoE-rich remnant lipoproteins, lipoprotein lipase, α2-macroglobulin/protease complexes, plasminogen activator/inhibitor complexes, the active protease tissue-type plasminogen activator and exotoxin A from Pseudomonas aeruginosa. Mice genetically deficient in LRP die early during gestation, underscoring the essential physiological role of this gene in vivo. To study the effect of LRP deficiency at the cellular level, we have used Pseudomonas exotoxin A (PEA) to select murine embryonic fibroblasts that are genetically deficient in LRP. Our results demon-strate that this single gene defect is sufficient to confer resistance to PEA on cultured cells. In addition, embryonic flbroblasts lacking LRP are unable to bind, internalize and degrade methylamine-activated α2-macroglobulin and complexes of urokinase with plasminogen activator inhibitor-1. Furthermore, cellular uptake and degradation of receptor-associated protein, a 39 kDa accessory protein of LRP, is reduced by 90{\%} in the absence of LRP. These results provide genetic evidence for the multifunctional nature of LRP and its crucial role in protease/inhibitor complex metabolism.",
keywords = "α2-macroglobulin, ApoE, Homologous recombination, Pseudomonas exotoxin A",
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AU - Herz, Joachim

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N2 - The low density lipoprotein receptor-related protein (LRP) is a large multifunctional receptor implicated in the cellular uptake of functionally diverse ligands. Biochemical evidence suggests that LRP is a clearance receptor for apoE-rich remnant lipoproteins, lipoprotein lipase, α2-macroglobulin/protease complexes, plasminogen activator/inhibitor complexes, the active protease tissue-type plasminogen activator and exotoxin A from Pseudomonas aeruginosa. Mice genetically deficient in LRP die early during gestation, underscoring the essential physiological role of this gene in vivo. To study the effect of LRP deficiency at the cellular level, we have used Pseudomonas exotoxin A (PEA) to select murine embryonic fibroblasts that are genetically deficient in LRP. Our results demon-strate that this single gene defect is sufficient to confer resistance to PEA on cultured cells. In addition, embryonic flbroblasts lacking LRP are unable to bind, internalize and degrade methylamine-activated α2-macroglobulin and complexes of urokinase with plasminogen activator inhibitor-1. Furthermore, cellular uptake and degradation of receptor-associated protein, a 39 kDa accessory protein of LRP, is reduced by 90% in the absence of LRP. These results provide genetic evidence for the multifunctional nature of LRP and its crucial role in protease/inhibitor complex metabolism.

AB - The low density lipoprotein receptor-related protein (LRP) is a large multifunctional receptor implicated in the cellular uptake of functionally diverse ligands. Biochemical evidence suggests that LRP is a clearance receptor for apoE-rich remnant lipoproteins, lipoprotein lipase, α2-macroglobulin/protease complexes, plasminogen activator/inhibitor complexes, the active protease tissue-type plasminogen activator and exotoxin A from Pseudomonas aeruginosa. Mice genetically deficient in LRP die early during gestation, underscoring the essential physiological role of this gene in vivo. To study the effect of LRP deficiency at the cellular level, we have used Pseudomonas exotoxin A (PEA) to select murine embryonic fibroblasts that are genetically deficient in LRP. Our results demon-strate that this single gene defect is sufficient to confer resistance to PEA on cultured cells. In addition, embryonic flbroblasts lacking LRP are unable to bind, internalize and degrade methylamine-activated α2-macroglobulin and complexes of urokinase with plasminogen activator inhibitor-1. Furthermore, cellular uptake and degradation of receptor-associated protein, a 39 kDa accessory protein of LRP, is reduced by 90% in the absence of LRP. These results provide genetic evidence for the multifunctional nature of LRP and its crucial role in protease/inhibitor complex metabolism.

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