| Autor: |
Chantal Maghames, Anton Gartner, Helene Trauchessec, María L. Martínez-Chantar, Orsolya Leidecker, Aurélien Perrin, Dimitris P. Xirodimas, Aymeric P. Bailly, Marina Serrano-Macia |
| Jazyk: |
angličtina |
| Rok vydání: |
2019 |
| Předmět: |
|
| DOI: |
10.1101/583864 |
| Popis: |
SummaryUbiquitin and ubiquitin-like chains are finely balanced by the action of conjugating and de-conjugating enzymes. Alterations in this balance trigger signalling events required for the response to stress conditions and are often observed in pathologies. How such changes are detected is not well-understood. We show that upon DNA damage the induction of the de-NEDDylating enzyme NEDP1 restricts the formation of poly-NEDD8 chains, mainly through lysines K11/K48. This promotes APAF1 oligomerisation and apoptosis induction, a step that requires the HSP70 ATPase activity. We found that HSP70 binds to NEDD8 and in vitro, mono-NEDD8 stimulates the ATPase activity of HSP70, counteracted upon poly-NEDDylation. This effect is independent of NEDD8 conjugation onto substrates. The studies identify the HSP70 chaperone as sensor of changes in the NEDD8 cycle, providing mechanistic insights for a cytoplasmic role of NEDD8 in the DNA damage induced apoptosis. They also indicate that the balance between mono- versus poly-NEDDylation is a regulatory module of HSP70 function. The above findings may be important in tumorigenesis, as we find that NEDP1 levels are downregulated in Hepatocellular Carcinoma with concomitant accumulation of NEDD8 conjugates. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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