Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling

Soluble klotho, the shed ectodomain of the antiaging membrane protein α-klotho, is a pleiotropic endocrine/paracrine factor with no known receptors and poorly understood mechanism of action. Soluble klotho down-regulates growth factor-driven PI3K signaling, contributing to extension of lifespan, car...

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Detalhes bibliográficos
Autores: Dalton, George, An, Sung-Wan, Al-Juboori, Saif I., Nischan, Nicole, Yoon, Joonho, Dobrinskikh, Evgenia, Hilgemann, Donald W., Xie, Jian, Luby-Phelps, Kate, Kohler, Jennifer J., Birnbaumer, Lutz, Huang, Chou-Long
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2017
País:Argentina
Recursos:Consejo Nacional de Investigaciones Científicas y Técnicas
Repositorio:CONICET Digital (CONICET)
Idioma:inglés
OAI Identifier:oai:ri.conicet.gov.ar:11336/47856
Acesso em linha:http://hdl.handle.net/11336/47856
Access Level:acceso abierto
Palavra-chave:GANGLIOSIDES
LIPID RAFTS
SIALIC ACIDS
SOLUBLE KLOTHO
TRPC6
https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
Descrição
Resumo:Soluble klotho, the shed ectodomain of the antiaging membrane protein α-klotho, is a pleiotropic endocrine/paracrine factor with no known receptors and poorly understood mechanism of action. Soluble klotho down-regulates growth factor-driven PI3K signaling, contributing to extension of lifespan, cardioprotection, and tumor inhibition. Here we show that soluble klotho binds membrane lipid rafts. Klotho binding to rafts alters lipid organization, decreases membrane´s propensity to form large ordered domains for endocytosis, and down-regulates raft-dependent PI3K/Akt signaling. We identify α2-3-sialyllactose present in the glycan of monosialogangliosides as targets of soluble klotho. α2-3-Sialyllactose is a common motif of glycans. To explain why klotho preferentially targets lipid rafts we show that clustering of gangliosides in lipid rafts is important. In vivo, raft-dependent PI3K signaling is up-regulated in klotho-deficient mouse hearts vs. wild-type hearts. Our results identify ganglioside-enriched lipid rafts to be receptors that mediate soluble klotho regulation of PI3K signaling. Targeting sialic acids may be a general mechanism for pleiotropic actions of soluble klotho.

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