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

Seung-Kuy Cha; Bernardo Ortega; Hiroshi Kurosu; Kevin P Rosenblatt; Makoto Kuro-O; Chou-Long Huang

doi:10.1073/pnas.0803223105

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

Journal article

Open access

Peer reviewed

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

Seung-Kuy Cha, Bernardo Ortega, Hiroshi Kurosu, Kevin P Rosenblatt, Makoto Kuro-O and Chou-Long Huang

Proceedings of the National Academy of Sciences - PNAS, Vol.105(28), pp.9805-9810

07/15/2008

DOI: 10.1073/pnas.0803223105

PMCID: PMC2474477

PMID: 18606998

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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 Ca(2+) 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 beta-galactoside alpha2,6-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 alpha2,6-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.

Animals

Calcium Channels - metabolism

Cell Line

Cricetinae

Galectin 1 - metabolism

Glucuronidase - metabolism

Glucuronidase - physiology

Membrane Proteins - metabolism

Mice

Mice, Knockout

Sialic Acids - metabolism

Sialyltransferases

TRPV Cation Channels - metabolism

Details

Title: Subtitle: Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1
Creators: Seung-Kuy Cha - The University of Texas Southwestern Medical Center
Bernardo Ortega - The University of Texas at Dallas
Hiroshi Kurosu - The University of Texas Southwestern Medical Center
Kevin P Rosenblatt - The University of Texas Southwestern Medical Center
Makoto Kuro-O - The University of Texas Southwestern Medical Center
Chou-Long Huang - Internal Medicine
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.105(28), pp.9805-9810
DOI: 10.1073/pnas.0803223105
PMID: 18606998
PMCID: PMC2474477
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Grant note: DK20543 / NIDDK NIH HHS R01 AG019712 / NIA NIH HHS GM62116 / NIGMS NIH HHS R01 AG019712-07 / NIA NIH HHS P01 DK020543 / NIDDK NIH HHS R01 AG025326-04 / NIA NIH HHS R01 AG025326 / NIA NIH HHS AG19712 / NIA NIH HHS R01 DK059530 / NIDDK NIH HHS DK59530 / NIDDK NIH HHS AG25326 / NIA NIH HHS U54 GM062116 / NIGMS NIH HHS
Language: English
Date published: 07/15/2008
Academic Unit: Nephrology; Internal Medicine
Record Identifier: 9984360050002771

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