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

Katalin Bartos; Suresh Krishna Ramakrishnan; Sophie Braga-Lagache; Barbara Hänzi; Fanny Durussel; Arjun Prakash Sridharan; Yao Zhu; David Sheehan; Nancy E Hynes; Olivier Bonny; Matthias B Moor

doi:10.1007/s12079-022-00710-1

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

J Cell Commun Signal. 2023 Sep;17(3):705-722. doi: 10.1007/s12079-022-00710-1. Epub 2022 Nov 25.

Authors

Katalin Bartos^#^{1

2}, Suresh Krishna Ramakrishnan^#^{2

3}, Sophie Braga-Lagache⁴, Barbara Hänzi³, Fanny Durussel³, Arjun Prakash Sridharan⁵, Yao Zhu^{5

6}, David Sheehan^{5

7}, Nancy E Hynes⁸, Olivier Bonny^{2

3

9

10}, Matthias B Moor^{11

12

13}

Affiliations

¹ Department of Nephrology and Hypertension, Bern University Hospital and Department of Biomedical Research, University of Bern, Freiburgstrasse 15, 3010, Bern, Switzerland.
² National Center of Competence in Research (NCCR) Kidney Control of Homeostasis (Kidney.CH), University of Zurich, Zurich, Switzerland.
³ Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland.
⁴ Proteomics and Mass Spectrometry Core Facility, Department for Biomedical Research (DBMR), University of Berne, Berne, Switzerland.
⁵ Proteomic Research Group, School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland.
⁶ School of Food and Nutritional Sciences, University College Cork, Cork, Ireland.
⁷ Department of Chemistry, College of Arts and Sciences, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates.
⁸ Friedrich Miescher Institute for Biomedical Research and University of Basel, Basel, Switzerland.
⁹ Service of Nephrology, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland.
¹⁰ Service of Nephrology, Department of Medicine, Hôpital Fribourgeois, Fribourg, Switzerland.
¹¹ Department of Nephrology and Hypertension, Bern University Hospital and Department of Biomedical Research, University of Bern, Freiburgstrasse 15, 3010, Bern, Switzerland. matthias.moor@dbmr.unibe.ch.
¹² National Center of Competence in Research (NCCR) Kidney Control of Homeostasis (Kidney.CH), University of Zurich, Zurich, Switzerland. matthias.moor@dbmr.unibe.ch.
¹³ Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland. matthias.moor@dbmr.unibe.ch.

^# Contributed equally.

Abstract

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.

Keywords: FGFR; Phosphatases; Redox proteomics; RhoA; RhoGDI1; Signal transduction.

Abstract

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