Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1

Seungkuy Cha, Bernardo Ortega, Hiroshi Kurosu, Kevin P. Rosenblatt, Makoto Kuro-o, Chou Long Huang

Research output: Contribution to journalArticle

285 Citations (Scopus)

Abstract

Klotho is a mammalian senescence-suppression protein that has homology with glycosidases. The extracellular domain of Klotho is secreted into urine and blood and may function as a humoral factor. Klotho-deficient mice have accelerated aging and imbalance of ion homeostasis. Klotho treatment increases cell-surface abundance of the renal epithelial Ca2+ channel TRPV5 by modifying its N-linked glycans. However, the precise sugar substrate and mechanism for regulation by Klotho is not known. Here, we report that the extracellular domain of Klotho activates plasma-membrane resident TRPV5 through removing terminal sialic acids from their glycan chains. Removal of sialic acids exposes underlying disaccharide galactose-N-acetylglucosamine, a ligand for a ubiquitous galactoside-binding lectin galectin-1. Binding to galectin-1 lattice at the extracellular surface leads to accumulation of functional TRPV5 on the plasma membrane. Knockdown of β-galactoside α2,6-sialyltransferase (ST6Gal-1) by RNA interference, but not other sialyltransferases, in a human cell line prevents the regulation by Klotho. Moreover, the regulation by Klotho is absent in a hamster cell line that lacks endogenous ST6Gal-1, but is restored by forced expression of recombinant ST6Gal-1. Thus, Klotho participates in specific removal of α2,6-linked sialic acids and regulates cell surface retention of TRPV5 through this activity. This action of Klotho represents a novel mechanism for regulation of the activity of cell-surface glycoproteins and likely contributes to maintenance of calcium balance by Klotho.

Original languageEnglish
Pages (from-to)9805-9810
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number28
DOIs
Publication statusPublished - 2008 Jul 15

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Galectin 1
Sialic Acids
N-Acetylneuraminic Acid
Sialyltransferases
Polysaccharides
Cell Membrane
Galactosides
Cell Line
Acetylglucosamine
Disaccharides
Glycoside Hydrolases
Membrane Glycoproteins
RNA Interference
Galactose
Cricetinae
Homeostasis
Maintenance
Urine
Ions
Ligands

All Science Journal Classification (ASJC) codes

  • General

Cite this

Cha, Seungkuy ; Ortega, Bernardo ; Kurosu, Hiroshi ; Rosenblatt, Kevin P. ; Kuro-o, Makoto ; Huang, Chou Long. / Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 28. pp. 9805-9810.
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title = "Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1",
abstract = "Klotho is a mammalian senescence-suppression protein that has homology with glycosidases. The extracellular domain of Klotho is secreted into urine and blood and may function as a humoral factor. Klotho-deficient mice have accelerated aging and imbalance of ion homeostasis. Klotho treatment increases cell-surface abundance of the renal epithelial Ca2+ channel TRPV5 by modifying its N-linked glycans. However, the precise sugar substrate and mechanism for regulation by Klotho is not known. Here, we report that the extracellular domain of Klotho activates plasma-membrane resident TRPV5 through removing terminal sialic acids from their glycan chains. Removal of sialic acids exposes underlying disaccharide galactose-N-acetylglucosamine, a ligand for a ubiquitous galactoside-binding lectin galectin-1. Binding to galectin-1 lattice at the extracellular surface leads to accumulation of functional TRPV5 on the plasma membrane. Knockdown of β-galactoside α2,6-sialyltransferase (ST6Gal-1) by RNA interference, but not other sialyltransferases, in a human cell line prevents the regulation by Klotho. Moreover, the regulation by Klotho is absent in a hamster cell line that lacks endogenous ST6Gal-1, but is restored by forced expression of recombinant ST6Gal-1. Thus, Klotho participates in specific removal of α2,6-linked sialic acids and regulates cell surface retention of TRPV5 through this activity. This action of Klotho represents a novel mechanism for regulation of the activity of cell-surface glycoproteins and likely contributes to maintenance of calcium balance by Klotho.",
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Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1. / Cha, Seungkuy; Ortega, Bernardo; Kurosu, Hiroshi; Rosenblatt, Kevin P.; Kuro-o, Makoto; Huang, Chou Long.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 28, 15.07.2008, p. 9805-9810.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1

AU - Cha, Seungkuy

AU - Ortega, Bernardo

AU - Kurosu, Hiroshi

AU - Rosenblatt, Kevin P.

AU - Kuro-o, Makoto

AU - Huang, Chou Long

PY - 2008/7/15

Y1 - 2008/7/15

N2 - Klotho is a mammalian senescence-suppression protein that has homology with glycosidases. The extracellular domain of Klotho is secreted into urine and blood and may function as a humoral factor. Klotho-deficient mice have accelerated aging and imbalance of ion homeostasis. Klotho treatment increases cell-surface abundance of the renal epithelial Ca2+ channel TRPV5 by modifying its N-linked glycans. However, the precise sugar substrate and mechanism for regulation by Klotho is not known. Here, we report that the extracellular domain of Klotho activates plasma-membrane resident TRPV5 through removing terminal sialic acids from their glycan chains. Removal of sialic acids exposes underlying disaccharide galactose-N-acetylglucosamine, a ligand for a ubiquitous galactoside-binding lectin galectin-1. Binding to galectin-1 lattice at the extracellular surface leads to accumulation of functional TRPV5 on the plasma membrane. Knockdown of β-galactoside α2,6-sialyltransferase (ST6Gal-1) by RNA interference, but not other sialyltransferases, in a human cell line prevents the regulation by Klotho. Moreover, the regulation by Klotho is absent in a hamster cell line that lacks endogenous ST6Gal-1, but is restored by forced expression of recombinant ST6Gal-1. Thus, Klotho participates in specific removal of α2,6-linked sialic acids and regulates cell surface retention of TRPV5 through this activity. This action of Klotho represents a novel mechanism for regulation of the activity of cell-surface glycoproteins and likely contributes to maintenance of calcium balance by Klotho.

AB - Klotho is a mammalian senescence-suppression protein that has homology with glycosidases. The extracellular domain of Klotho is secreted into urine and blood and may function as a humoral factor. Klotho-deficient mice have accelerated aging and imbalance of ion homeostasis. Klotho treatment increases cell-surface abundance of the renal epithelial Ca2+ channel TRPV5 by modifying its N-linked glycans. However, the precise sugar substrate and mechanism for regulation by Klotho is not known. Here, we report that the extracellular domain of Klotho activates plasma-membrane resident TRPV5 through removing terminal sialic acids from their glycan chains. Removal of sialic acids exposes underlying disaccharide galactose-N-acetylglucosamine, a ligand for a ubiquitous galactoside-binding lectin galectin-1. Binding to galectin-1 lattice at the extracellular surface leads to accumulation of functional TRPV5 on the plasma membrane. Knockdown of β-galactoside α2,6-sialyltransferase (ST6Gal-1) by RNA interference, but not other sialyltransferases, in a human cell line prevents the regulation by Klotho. Moreover, the regulation by Klotho is absent in a hamster cell line that lacks endogenous ST6Gal-1, but is restored by forced expression of recombinant ST6Gal-1. Thus, Klotho participates in specific removal of α2,6-linked sialic acids and regulates cell surface retention of TRPV5 through this activity. This action of Klotho represents a novel mechanism for regulation of the activity of cell-surface glycoproteins and likely contributes to maintenance of calcium balance by Klotho.

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U2 - 10.1073/pnas.0803223105

DO - 10.1073/pnas.0803223105

M3 - Article

VL - 105

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EP - 9810

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

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