Renal FGF23 signaling depends on redox protein Memo1 and promotes orthovanadate-sensitive protein phosphotyrosyl phosphatase activity.

Memo1 deletion in mice causes premature aging and an unbalanced metabolism partially resembling Fgf23 and Klotho loss-of-function animals. We report a role for Memo's redox function in renal FGF23-Klotho signaling using mice with postnatally induced Memo deficiency in the whole body (cKO). Memo cKO mice showed impaired FGF23-driven renal ERK phosphorylation and transcriptional responses. FGF23 actions involved activation of oxidation-sensitive protein phosphotyrosyl phosphatases in the kidney. Redox proteomics revealed excessive thiols of Rho-GDP dissociation inhibitor 1 (Rho-GDI1) in Memo cKO, and we detected a functional interaction between Memo's redox function and oxidation at Rho-GDI1 Cys79. In isolated cellular systems, Rho-GDI1 did not directly affect FGF23-driven cell signaling, but we detected disturbed Rho-GDI1 dependent small Rho-GTPase protein abundance and activity in the kidney of Memo cKO mice. Collectively, this study reveals previously unknown layers in the regulation of renal FGF23 signaling and connects Memo with the network of small Rho-GTPases

Redox protein Memo 1 coordinates FGF23-driven signaling and small Rho-GTPases in the mouse kidney

Memo promotes receptor tyrosine kinase (RTK) signaling by unknown mechanisms. Memo1 deletion in mice causes premature aging and unbalanced metabolism partially resembling Fgf23 and Klotho loss-of-function animals. Here, we report a role for Memo’s redox function in FGF23-driven RTK signaling in the kidney. Postnatally Memo-deficient (cKO) and floxed controls were treated with FGF23 or vehicle, followed by molecular and biochemical analyses. Findings were validated using cell culture and recombinant proteins. Memo cKO mice showed impaired renal ERK phosphorylation and transcriptional responses to FGF23. Redox proteomics revealed excessive thiols of Rho-GDP dissociation inhibitor 1 (Rho-GDI1). Renal RhoA abundance and activity were increased in Memo cKO. Immunoprecipitation analysis showed an association between Memo and Rho-GDI1. We confirmed an interaction between the two proteins, with Memo-dependent irreversible oxidation at Rho-GDI1 Cys79 in cell-free conditions. Collectively, our findings reveal that redox protein Memo promotes renal FGF23 signaling together with oxidative modulation of the Rho-GTPase network