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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*,?
+Author Affiliations
Departments of *Medicine and ?Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390
Communicated by Melanie H. Cobb, University of Texas Southwestern Medical Center, Dallas, TX, April 16, 2008 (received for review December 26, 2007)
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.
Footnotes
?To whom correspondence should be addressed. E-mail: chou-long.huang@utsouthwestern.edu Author contributions: S.-K.C., B.O., H.K., M.K.-o., and C.-L.H. designed research; S.-K.C., B.O., and H.K. performed research; K.P.R. contributed new reagents/analytic tools; S.-K.C., B.O., H.K., M.K.-o., and C.-L.H. analyzed data; and S.-K.C., M.K.-o., and C.-L.H. wrote the paper.
↵ ?S.-K.C. and B.O. contributed equally to this work.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0803223105/DCSupplemental.
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Seung-Kuy Cha*,?, Bernardo Ortega*,?, Hiroshi Kurosu?, Kevin P. Rosenblatt?, Makoto Kuro-o?, and Chou-Long Huang*,?
+Author Affiliations
Departments of *Medicine and ?Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390
Communicated by Melanie H. Cobb, University of Texas Southwestern Medical Center, Dallas, TX, April 16, 2008 (received for review December 26, 2007)
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.
Footnotes
?To whom correspondence should be addressed. E-mail: chou-long.huang@utsouthwestern.edu Author contributions: S.-K.C., B.O., H.K., M.K.-o., and C.-L.H. designed research; S.-K.C., B.O., and H.K. performed research; K.P.R. contributed new reagents/analytic tools; S.-K.C., B.O., H.K., M.K.-o., and C.-L.H. analyzed data; and S.-K.C., M.K.-o., and C.-L.H. wrote the paper.
↵ ?S.-K.C. and B.O. contributed equally to this work.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0803223105/DCSupplemental.
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