JNK mediates cell death by promoting the ubiquitination of the apurinic/apyrimidinic endonuclease APE1
The c-Jun-NH2-terminal kinases (JNKs) regulate cell death, generally through the direct phosphorylation of both pro- and anti-apoptotic substrates. In this report, we demonstrate an alternate mechanism of JNK-mediated cell death involving the anti-apoptotic protein human apurinic/apyrimidinic endonu...
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| Main Authors: | , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
2023
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| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/171372 |
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| Institution: | Nanyang Technological University |
| Language: | English |
| Summary: | The c-Jun-NH2-terminal kinases (JNKs) regulate cell death, generally through the direct phosphorylation of both pro- and anti-apoptotic substrates. In this report, we demonstrate an alternate mechanism of JNK-mediated cell death involving the anti-apoptotic protein human apurinic/apyrimidinic endonuclease 1 (APE1). Treatment of cells with a variety of genotoxic stresses enhanced APE1-JNK (all isoforms of JNK1 or JNK2) interaction, specifically in cells undergoing apoptosis. Steady-state APE1 levels were decreased in these cells, in which APE1 is ubiquitinated and degraded in a JNK-dependent manner. Absence of JNKs reduced APE1 ubiquitination and increased its abundance. Mechanistically, the E3 ligase ITCH associates with both APE1 and JNK and is necessary for JNK-dependent APE1 ubiquitination and degradation. Structural models of the JNK-APE1 interaction support the observation of enhanced association of the complex in the presence of ubiquitin. The data together show a mechanism of JNK-mediated cell death by the degradation of APE1 through ITCH. |
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