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Klotho interferes with a novel FGF-signalling pathway and insulin/Igf-like signalling to improve longevity and stress resistance in Caenorhabditis elegans.

Château MT, Araiz C, Descamps S, Galas S - Aging (Albany NY) (2010)

Bottom Line: While membrane-bound Klotho, which is primarily expressed in the kidney, acts as an obligate co-receptor of FGF23 to regulate phosphate homeostasis, secreted Klotho, resulting from the shedding of the KL1-KL2 ectodomain into the bloodstream, inhibits Insulin/IGF1 signalling.Besides revealing a new post-developmental role for EGL-17, our data suggest that the KL1 form of Klotho is involved in FGF23-independent FGF signalling.While the regulation of longevity requires functional DAF-2/DAF-16 signalling, the control of oxidative stress resistance involves a DAF-2- independent, DAF-16-dependent pathway, suggesting that Klotho may target either DAF-2 or DAF-16, depending of environmental conditions.

View Article: PubMed Central - PubMed

Affiliation: University of Montpellier1, Faculty of Pharmacy and Pharmaceutical Sciences, F-34093 Montpellier Cedex 5, France.

ABSTRACT
Klotho exerts anti-aging properties in mammals in two different ways. While membrane-bound Klotho, which is primarily expressed in the kidney, acts as an obligate co-receptor of FGF23 to regulate phosphate homeostasis, secreted Klotho, resulting from the shedding of the KL1-KL2 ectodomain into the bloodstream, inhibits Insulin/IGF1 signalling. However, the underlying molecular mechanisms are not fully understood. Here, we investigated the biological role of Klotho in Caenorhabditis elegans. Two redundant homologues of the klotho gene exist in C. elegans and encode predicted proteins homologous to the  glucosidase-like KL1 domain of mammalian Klotho. We have used a genetic approach to investigate the functional activity of Klotho in C. elegans. Here, we report that whereas Klotho requires EGL-15 (FGFR) and EGL-17 to promote longevity and oxidative stress resistance, it is not involved in the regulation of fluid homeostasis, controlled by LET-756. Besides revealing a new post-developmental role for EGL-17, our data suggest that the KL1 form of Klotho is involved in FGF23-independent FGF signalling. We also report a genetic interaction between Klotho and the DAF-2 (Ins/IGF1R)/DAF-16 (FOXO) pathway. While the regulation of longevity requires functional DAF-2/DAF-16 signalling, the control of oxidative stress resistance involves a DAF-2- independent, DAF-16-dependent pathway, suggesting that Klotho may target either DAF-2 or DAF-16, depending of environmental conditions. Thus, the predictive KL1 form of Klotho appears to crosstalk with both FGF and Insulin/IGF1/FOXO pathways to exert anti-aging properties in C. elegans.

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In adult worms the FGFR EGL-15(5A) targeted for activation by the Klotho KL1 isoform can allow EGL-17 ligand binding. Under physiological conditions, the Klotho/EGL-15/EGL-17 complex constitutively represses the DAF-2 (Insulin/Igf-like) receptors by a still unknown pathway. Such complexes may induce DAF-16 (FOXO) de-repression and subsequent overexpression of longevity factors, such as antioxidant enzymes. When worms have to cope with a potent stress, the Klotho/EGL-15/EGL-17 complex may directly activate DAF-16 by a DAF-2-independent pathway (dashed line). Such activation mechanism remains to be elucidated.
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Figure 6: In adult worms the FGFR EGL-15(5A) targeted for activation by the Klotho KL1 isoform can allow EGL-17 ligand binding. Under physiological conditions, the Klotho/EGL-15/EGL-17 complex constitutively represses the DAF-2 (Insulin/Igf-like) receptors by a still unknown pathway. Such complexes may induce DAF-16 (FOXO) de-repression and subsequent overexpression of longevity factors, such as antioxidant enzymes. When worms have to cope with a potent stress, the Klotho/EGL-15/EGL-17 complex may directly activate DAF-16 by a DAF-2-independent pathway (dashed line). Such activation mechanism remains to be elucidated.

Mentions: In summary, our data suggest that Klotho could target either worm DAF-2 or DAF-16, depending of environ-mental cues. Indeed, Klotho seems to constitutively repress DAF-2 throughout lifespan while it could also directly activate DAF-16 when the nematode has to cope with intense stress (Figure 6). Since a functional EGL-17/EGL-15(5A) signalling is required in all cases, the predicted KL1 form of Klotho appears to link FGF and Insulin/Igf-like pathways, in C. elegans. How these two pathways can crosstalk remains to be determined. A potential intermediate could be the adaptor protein SHC-1, homologue of human p52Shc, that has been recently reported to modulate lifespan and stress response in C. elegans. Indeed, SHC-1 was shown to repress DAF-2 by an unknown mechanism and to activate DAF-16 by a JNK-involved pathway [56].


Klotho interferes with a novel FGF-signalling pathway and insulin/Igf-like signalling to improve longevity and stress resistance in Caenorhabditis elegans.

Château MT, Araiz C, Descamps S, Galas S - Aging (Albany NY) (2010)

In adult worms the FGFR EGL-15(5A) targeted for activation by the Klotho KL1 isoform can allow EGL-17 ligand binding. Under physiological conditions, the Klotho/EGL-15/EGL-17 complex constitutively represses the DAF-2 (Insulin/Igf-like) receptors by a still unknown pathway. Such complexes may induce DAF-16 (FOXO) de-repression and subsequent overexpression of longevity factors, such as antioxidant enzymes. When worms have to cope with a potent stress, the Klotho/EGL-15/EGL-17 complex may directly activate DAF-16 by a DAF-2-independent pathway (dashed line). Such activation mechanism remains to be elucidated.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2984606&req=5

Figure 6: In adult worms the FGFR EGL-15(5A) targeted for activation by the Klotho KL1 isoform can allow EGL-17 ligand binding. Under physiological conditions, the Klotho/EGL-15/EGL-17 complex constitutively represses the DAF-2 (Insulin/Igf-like) receptors by a still unknown pathway. Such complexes may induce DAF-16 (FOXO) de-repression and subsequent overexpression of longevity factors, such as antioxidant enzymes. When worms have to cope with a potent stress, the Klotho/EGL-15/EGL-17 complex may directly activate DAF-16 by a DAF-2-independent pathway (dashed line). Such activation mechanism remains to be elucidated.
Mentions: In summary, our data suggest that Klotho could target either worm DAF-2 or DAF-16, depending of environ-mental cues. Indeed, Klotho seems to constitutively repress DAF-2 throughout lifespan while it could also directly activate DAF-16 when the nematode has to cope with intense stress (Figure 6). Since a functional EGL-17/EGL-15(5A) signalling is required in all cases, the predicted KL1 form of Klotho appears to link FGF and Insulin/Igf-like pathways, in C. elegans. How these two pathways can crosstalk remains to be determined. A potential intermediate could be the adaptor protein SHC-1, homologue of human p52Shc, that has been recently reported to modulate lifespan and stress response in C. elegans. Indeed, SHC-1 was shown to repress DAF-2 by an unknown mechanism and to activate DAF-16 by a JNK-involved pathway [56].

Bottom Line: While membrane-bound Klotho, which is primarily expressed in the kidney, acts as an obligate co-receptor of FGF23 to regulate phosphate homeostasis, secreted Klotho, resulting from the shedding of the KL1-KL2 ectodomain into the bloodstream, inhibits Insulin/IGF1 signalling.Besides revealing a new post-developmental role for EGL-17, our data suggest that the KL1 form of Klotho is involved in FGF23-independent FGF signalling.While the regulation of longevity requires functional DAF-2/DAF-16 signalling, the control of oxidative stress resistance involves a DAF-2- independent, DAF-16-dependent pathway, suggesting that Klotho may target either DAF-2 or DAF-16, depending of environmental conditions.

View Article: PubMed Central - PubMed

Affiliation: University of Montpellier1, Faculty of Pharmacy and Pharmaceutical Sciences, F-34093 Montpellier Cedex 5, France.

ABSTRACT
Klotho exerts anti-aging properties in mammals in two different ways. While membrane-bound Klotho, which is primarily expressed in the kidney, acts as an obligate co-receptor of FGF23 to regulate phosphate homeostasis, secreted Klotho, resulting from the shedding of the KL1-KL2 ectodomain into the bloodstream, inhibits Insulin/IGF1 signalling. However, the underlying molecular mechanisms are not fully understood. Here, we investigated the biological role of Klotho in Caenorhabditis elegans. Two redundant homologues of the klotho gene exist in C. elegans and encode predicted proteins homologous to the  glucosidase-like KL1 domain of mammalian Klotho. We have used a genetic approach to investigate the functional activity of Klotho in C. elegans. Here, we report that whereas Klotho requires EGL-15 (FGFR) and EGL-17 to promote longevity and oxidative stress resistance, it is not involved in the regulation of fluid homeostasis, controlled by LET-756. Besides revealing a new post-developmental role for EGL-17, our data suggest that the KL1 form of Klotho is involved in FGF23-independent FGF signalling. We also report a genetic interaction between Klotho and the DAF-2 (Ins/IGF1R)/DAF-16 (FOXO) pathway. While the regulation of longevity requires functional DAF-2/DAF-16 signalling, the control of oxidative stress resistance involves a DAF-2- independent, DAF-16-dependent pathway, suggesting that Klotho may target either DAF-2 or DAF-16, depending of environmental conditions. Thus, the predictive KL1 form of Klotho appears to crosstalk with both FGF and Insulin/IGF1/FOXO pathways to exert anti-aging properties in C. elegans.

Show MeSH
Related in: MedlinePlus