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Fyn Phosphorylates Transglutaminase 2 (Tgm2) and Modulates Autophagy and p53 Expression in the Development of Diabetic Kidney Disease

Autophagy is involved in the development of diabetic kidney disease (DKD), the leading cause of end-stage renal disease. The Fyn tyrosine kinase (Fyn) suppresses autophagy in the muscle. However, its role in kidney autophagic processes is unclear. Here, we examined the role of Fyn kinase in autophag...

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Autores principales: Uehara, Ryota, Yamada, Eijiro, Okada, Shuichi, Bastie, Claire C., Maeshima, Akito, Ikeuchi, Hidekazu, Horiguchi, Kazuhiko, Yamada, Masanobu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10136856/
https://www.ncbi.nlm.nih.gov/pubmed/37190106
http://dx.doi.org/10.3390/cells12081197
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author Uehara, Ryota
Yamada, Eijiro
Okada, Shuichi
Bastie, Claire C.
Maeshima, Akito
Ikeuchi, Hidekazu
Horiguchi, Kazuhiko
Yamada, Masanobu
author_facet Uehara, Ryota
Yamada, Eijiro
Okada, Shuichi
Bastie, Claire C.
Maeshima, Akito
Ikeuchi, Hidekazu
Horiguchi, Kazuhiko
Yamada, Masanobu
author_sort Uehara, Ryota
collection PubMed
description Autophagy is involved in the development of diabetic kidney disease (DKD), the leading cause of end-stage renal disease. The Fyn tyrosine kinase (Fyn) suppresses autophagy in the muscle. However, its role in kidney autophagic processes is unclear. Here, we examined the role of Fyn kinase in autophagy in proximal renal tubules both in vivo and in vitro. Phospho-proteomic analysis revealed that transglutaminase 2 (Tgm2), a protein involved in the degradation of p53 in the autophagosome, is phosphorylated on tyrosine 369 (Y369) by Fyn. Interestingly, we found that Fyn-dependent phosphorylation of Tgm2 regulates autophagy in proximal renal tubules in vitro, and that p53 expression is decreased upon autophagy in Tgm2-knockdown proximal renal tubule cell models. Using streptozocin (STZ)-induced hyperglycemic mice, we confirmed that Fyn regulated autophagy and mediated p53 expression via Tgm2. Taken together, these data provide a molecular basis for the role of the Fyn–Tgm2–p53 axis in the development of DKD.
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spelling pubmed-101368562023-04-28 Fyn Phosphorylates Transglutaminase 2 (Tgm2) and Modulates Autophagy and p53 Expression in the Development of Diabetic Kidney Disease Uehara, Ryota Yamada, Eijiro Okada, Shuichi Bastie, Claire C. Maeshima, Akito Ikeuchi, Hidekazu Horiguchi, Kazuhiko Yamada, Masanobu Cells Article Autophagy is involved in the development of diabetic kidney disease (DKD), the leading cause of end-stage renal disease. The Fyn tyrosine kinase (Fyn) suppresses autophagy in the muscle. However, its role in kidney autophagic processes is unclear. Here, we examined the role of Fyn kinase in autophagy in proximal renal tubules both in vivo and in vitro. Phospho-proteomic analysis revealed that transglutaminase 2 (Tgm2), a protein involved in the degradation of p53 in the autophagosome, is phosphorylated on tyrosine 369 (Y369) by Fyn. Interestingly, we found that Fyn-dependent phosphorylation of Tgm2 regulates autophagy in proximal renal tubules in vitro, and that p53 expression is decreased upon autophagy in Tgm2-knockdown proximal renal tubule cell models. Using streptozocin (STZ)-induced hyperglycemic mice, we confirmed that Fyn regulated autophagy and mediated p53 expression via Tgm2. Taken together, these data provide a molecular basis for the role of the Fyn–Tgm2–p53 axis in the development of DKD. MDPI 2023-04-20 /pmc/articles/PMC10136856/ /pubmed/37190106 http://dx.doi.org/10.3390/cells12081197 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Uehara, Ryota
Yamada, Eijiro
Okada, Shuichi
Bastie, Claire C.
Maeshima, Akito
Ikeuchi, Hidekazu
Horiguchi, Kazuhiko
Yamada, Masanobu
Fyn Phosphorylates Transglutaminase 2 (Tgm2) and Modulates Autophagy and p53 Expression in the Development of Diabetic Kidney Disease
title Fyn Phosphorylates Transglutaminase 2 (Tgm2) and Modulates Autophagy and p53 Expression in the Development of Diabetic Kidney Disease
title_full Fyn Phosphorylates Transglutaminase 2 (Tgm2) and Modulates Autophagy and p53 Expression in the Development of Diabetic Kidney Disease
title_fullStr Fyn Phosphorylates Transglutaminase 2 (Tgm2) and Modulates Autophagy and p53 Expression in the Development of Diabetic Kidney Disease
title_full_unstemmed Fyn Phosphorylates Transglutaminase 2 (Tgm2) and Modulates Autophagy and p53 Expression in the Development of Diabetic Kidney Disease
title_short Fyn Phosphorylates Transglutaminase 2 (Tgm2) and Modulates Autophagy and p53 Expression in the Development of Diabetic Kidney Disease
title_sort fyn phosphorylates transglutaminase 2 (tgm2) and modulates autophagy and p53 expression in the development of diabetic kidney disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10136856/
https://www.ncbi.nlm.nih.gov/pubmed/37190106
http://dx.doi.org/10.3390/cells12081197
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