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ATG4D is the main ATG8 delipidating enzyme in mammalian cells and protects against cerebellar neurodegeneration

Despite the great advances in autophagy research in the last years, the specific functions of the four mammalian Atg4 proteases (ATG4A-D) remain unclear. In yeast, Atg4 mediates both Atg8 proteolytic activation, and its delipidation. However, it is not clear how these two roles are distributed along...

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Autores principales: Tamargo-Gómez, Isaac, Martínez-García, Gemma G., Suárez, María F., Rey, Verónica, Fueyo, Antonio, Codina-Martínez, Helena, Bretones, Gabriel, Caravia, Xurde M., Morel, Etienne, Dupont, Nicolas, Cabo, Roberto, Tomás-Zapico, Cristina, Souquere, Sylvie, Pierron, Gerard, Codogno, Patrice, López-Otín, Carlos, Fernández, Álvaro F., Mariño, Guillermo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408152/
https://www.ncbi.nlm.nih.gov/pubmed/33795848
http://dx.doi.org/10.1038/s41418-021-00776-1
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author Tamargo-Gómez, Isaac
Martínez-García, Gemma G.
Suárez, María F.
Rey, Verónica
Fueyo, Antonio
Codina-Martínez, Helena
Bretones, Gabriel
Caravia, Xurde M.
Morel, Etienne
Dupont, Nicolas
Cabo, Roberto
Tomás-Zapico, Cristina
Souquere, Sylvie
Pierron, Gerard
Codogno, Patrice
López-Otín, Carlos
Fernández, Álvaro F.
Mariño, Guillermo
author_facet Tamargo-Gómez, Isaac
Martínez-García, Gemma G.
Suárez, María F.
Rey, Verónica
Fueyo, Antonio
Codina-Martínez, Helena
Bretones, Gabriel
Caravia, Xurde M.
Morel, Etienne
Dupont, Nicolas
Cabo, Roberto
Tomás-Zapico, Cristina
Souquere, Sylvie
Pierron, Gerard
Codogno, Patrice
López-Otín, Carlos
Fernández, Álvaro F.
Mariño, Guillermo
author_sort Tamargo-Gómez, Isaac
collection PubMed
description Despite the great advances in autophagy research in the last years, the specific functions of the four mammalian Atg4 proteases (ATG4A-D) remain unclear. In yeast, Atg4 mediates both Atg8 proteolytic activation, and its delipidation. However, it is not clear how these two roles are distributed along the members of the ATG4 family of proteases. We show that these two functions are preferentially carried out by distinct ATG4 proteases, being ATG4D the main delipidating enzyme. In mammalian cells, ATG4D loss results in accumulation of membrane-bound forms of mATG8s, increased cellular autophagosome number and reduced autophagosome average size. In mice, ATG4D loss leads to cerebellar neurodegeneration and impaired motor coordination caused by alterations in trafficking/clustering of GABA(A) receptors. We also show that human gene variants of ATG4D associated with neurodegeneration are not able to fully restore ATG4D deficiency, highlighting the neuroprotective role of ATG4D in mammals.
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spelling pubmed-84081522021-09-16 ATG4D is the main ATG8 delipidating enzyme in mammalian cells and protects against cerebellar neurodegeneration Tamargo-Gómez, Isaac Martínez-García, Gemma G. Suárez, María F. Rey, Verónica Fueyo, Antonio Codina-Martínez, Helena Bretones, Gabriel Caravia, Xurde M. Morel, Etienne Dupont, Nicolas Cabo, Roberto Tomás-Zapico, Cristina Souquere, Sylvie Pierron, Gerard Codogno, Patrice López-Otín, Carlos Fernández, Álvaro F. Mariño, Guillermo Cell Death Differ Article Despite the great advances in autophagy research in the last years, the specific functions of the four mammalian Atg4 proteases (ATG4A-D) remain unclear. In yeast, Atg4 mediates both Atg8 proteolytic activation, and its delipidation. However, it is not clear how these two roles are distributed along the members of the ATG4 family of proteases. We show that these two functions are preferentially carried out by distinct ATG4 proteases, being ATG4D the main delipidating enzyme. In mammalian cells, ATG4D loss results in accumulation of membrane-bound forms of mATG8s, increased cellular autophagosome number and reduced autophagosome average size. In mice, ATG4D loss leads to cerebellar neurodegeneration and impaired motor coordination caused by alterations in trafficking/clustering of GABA(A) receptors. We also show that human gene variants of ATG4D associated with neurodegeneration are not able to fully restore ATG4D deficiency, highlighting the neuroprotective role of ATG4D in mammals. Nature Publishing Group UK 2021-04-01 2021-09 /pmc/articles/PMC8408152/ /pubmed/33795848 http://dx.doi.org/10.1038/s41418-021-00776-1 Text en © The Author(s) 2021, corrected publication 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Tamargo-Gómez, Isaac
Martínez-García, Gemma G.
Suárez, María F.
Rey, Verónica
Fueyo, Antonio
Codina-Martínez, Helena
Bretones, Gabriel
Caravia, Xurde M.
Morel, Etienne
Dupont, Nicolas
Cabo, Roberto
Tomás-Zapico, Cristina
Souquere, Sylvie
Pierron, Gerard
Codogno, Patrice
López-Otín, Carlos
Fernández, Álvaro F.
Mariño, Guillermo
ATG4D is the main ATG8 delipidating enzyme in mammalian cells and protects against cerebellar neurodegeneration
title ATG4D is the main ATG8 delipidating enzyme in mammalian cells and protects against cerebellar neurodegeneration
title_full ATG4D is the main ATG8 delipidating enzyme in mammalian cells and protects against cerebellar neurodegeneration
title_fullStr ATG4D is the main ATG8 delipidating enzyme in mammalian cells and protects against cerebellar neurodegeneration
title_full_unstemmed ATG4D is the main ATG8 delipidating enzyme in mammalian cells and protects against cerebellar neurodegeneration
title_short ATG4D is the main ATG8 delipidating enzyme in mammalian cells and protects against cerebellar neurodegeneration
title_sort atg4d is the main atg8 delipidating enzyme in mammalian cells and protects against cerebellar neurodegeneration
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408152/
https://www.ncbi.nlm.nih.gov/pubmed/33795848
http://dx.doi.org/10.1038/s41418-021-00776-1
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