Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1.
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.
Cha
Seung-Kuy
SK
Departments of Medicine and Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Ortega
Bernardo
B
Kurosu
Hiroshi
H
Rosenblatt
Kevin P
KP
Kuro-O
Makoto
M
Huang
Chou-Long
CL
D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D002460:Cell Line; D006224:Cricetinae; D037483:Galectin 1 / Q000378:metabolism*; D005966:Glucuronidase / Q000378:metabolism* / Q000502:physiology; D000090265:Klotho Proteins; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D012794:Sialic Acids / Q000378:metabolism*; D012799:Sialyltransferases; D050916:TRPV Cation Channels / Q000378:metabolism*; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase
D015220:Calcium Channels; D037483:Galectin 1; D008565:Membrane Proteins; D012794:Sialic Acids; D050916:TRPV Cation Channels; C492240:Trpv5 protein, mouse; D012799:Sialyltransferases; D005966:Glucuronidase; D000090265:Klotho Proteins; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase