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

TLDR

Soluble klotho, the shed ectodomain of the anti‑aging protein α‑klotho, functions as an endocrine/paracrine factor that down‑regulates growth‑factor‑driven PI3K signaling, thereby extending lifespan, protecting the heart, and inhibiting tumors, and its activity involves the common glycan motif α2‑3‑sialyllactose. To explain klotho’s preference for lipid rafts, the authors show that clustering of gangliosides within these rafts is essential. The study demonstrates that soluble klotho binds to ganglioside‑enriched lipid rafts via α2‑3‑sialyllactose, remodels raft lipid organization to reduce large ordered domain formation, down‑regulates raft‑dependent PI3K/Akt signaling, and that klotho deficiency up‑regulates this pathway in mouse hearts, suggesting sialic acids as a general mechanism for klotho’s pleiotropic actions.

Abstract

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.