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lüll Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1 Cha SK; Ortega B; Kurosu H; Rosenblatt KP; Kuro-O M; Huang CLProc Natl Acad Sci U S A 2008[Jul]; 105 (28): 9805-10Klotho 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[MESH]|Calcium Channels/*metabolism[MESH]|Cell Line[MESH]|Cricetinae[MESH]|Galectin 1/*metabolism[MESH]|Glucuronidase/*metabolism/physiology[MESH]|Klotho Proteins[MESH]|Membrane Proteins/metabolism[MESH]|Mice[MESH]|Mice, Knockout[MESH]|Sialic Acids/*metabolism[MESH]|Sialyltransferases[MESH]|TRPV Cation Channels/*metabolism[MESH]|beta-D-Galactoside alpha 2-6-Sialyltransferase[MESH] |