Klotho is a substrate for alpha-, beta- and gamma-secretase.
Klotho is an anti-aging protein with different functions of the full-length membrane protein and the secreted hormone-like form. Using overexpression and knock-down approaches as well as embryonic fibroblasts of knock-out mice we present evidence that Klotho is shedded by the alpha-secretases ADAM10 and 17 as well as by the beta-secretase beta-APP cleaving enzyme 1. The remaining membrane-bound fragment is a substrate for regulated intramembrane proteolysis by gamma-secretase. Our data suggest that therapeutic approaches targeting these proteases should be carefully analyzed for potential side effects on Klotho-mediated physiological processes.
Bloch
Laura
L
Leibniz Institut für Altersforschung-Fritz Lipmann Institut, Beutenbergstr. 11, 07745 Jena, Germany.
Sineshchekova
Olga
O
Reichenbach
Daniela
D
Reiss
Karina
K
Saftig
Paul
P
Kuro-o
Makoto
M
Kaether
Christoph
C
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D005966:Glucuronidase / Q000378:metabolism*; D006801:Humans; D000090265:Klotho Proteins; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D013379:Substrate Specificity
D008565:Membrane Proteins; D005966:Glucuronidase; D000090265:Klotho Proteins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse; D000072198:ADAM17 Protein