ATG4D role in mAtg8s delipidation and neuroprotection
| Autor: | Guillermo Mariño, Isaac Tamargo-Gómez, Gemma G. Martínez-García, María F. Suárez, Álvaro F. Fernández |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
ATG8 GABARAP medicine.medical_treatment Autophagy-Related Proteins Biology Cleavage (embryo) Neuroprotection Article 03 medical and health sciences Macroautophagy medicine Autophagy Molecular Biology Protease 030102 biochemistry & molecular biology Disease genetics Neurodegeneration Cell Biology Autophagy-Related Protein 8 Family Proteases Neural ageing medicine.disease Yeast Cell biology 030104 developmental biology Neurological disorders |
| Zdroj: | Cell Death and Differentiation |
| ISSN: | 1554-8635 |
| Popis: | 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 GABAA 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. |
| Databáze: | OpenAIRE |
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