Parkin is an E3 ligase for the ubiquitin-like modifier FAT10, which inhibits Parkin activation and mitophagy
| Autor: | Nicola Catone, Florian Stengel, Carolin Sailer, Nicola D. Roverato, Marcus Groettrup, Annette Aichem |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Proteasome Endopeptidase Complex Parkinson's disease Ubiquitin-Protein Ligases General Biochemistry Genetics and Molecular Biology Parkin GTP Phosphohydrolases Substrate Specificity Mitochondrial Proteins 03 medical and health sciences 0302 clinical medicine Cytosol Ubiquitin ddc:570 Mitophagy medicine Humans Ubiquitins Neurons biology Cell Death Chemistry USE1 Ubiquitination Depolarization medicine.disease FAT10 ubiquitin-like modifier Parkin mitophagy Parkinson’s disease Ubiquitin ligase Cell biology nervous system diseases Mitochondria Protein Transport 030104 developmental biology HEK293 Cells Proteasome Proteolysis biology.protein Reactive Oxygen Species 030217 neurology & neurosurgery HeLa Cells |
| Zdroj: | Cell reports. 34(11) |
| ISSN: | 2211-1247 |
| Popis: | Parkin is an E3 ubiquitin ligase belonging to the RING-between-RING family. Mutations in the Parkin-encoding gene PARK2 are associated with familial Parkinson's disease. Here, we investigate the interplay between Parkin and the inflammatory cytokine-induced ubiquitin-like modifier FAT10. FAT10 targets hundreds of proteins for degradation by the 26S proteasome. We show that FAT10 gets conjugated to Parkin and mediates its degradation in a proteasome-dependent manner. Parkin binds to the E2 enzyme of FAT10 (USE1), auto-FAT10ylates itself, and facilitates FAT10ylation of the Parkin substrate Mitofusin2 in vitro and in cells, thus identifying Parkin as a FAT10 E3 ligase. On mitochondrial depolarization, FAT10ylation of Parkin inhibits its activation and ubiquitin-ligase activity causing impairment of mitophagy progression and aggravation of rotenone-mediated death of dopaminergic neuronal cells. In conclusion, FAT10ylation inhibits Parkin and mitophagy rendering FAT10 a likely inflammation-induced exacerbating factor and potential drug target for Parkinson's disease. published |
| Databáze: | OpenAIRE |
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