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...
| Main Authors: | , , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2023
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| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/171372 |
| _version_ | 1826112219957428224 |
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| author | Tabanifar, Bahareh Moorthy, Anbalagan Tsai, Heng Hang Kannan, Srinivasaraghavan Verma, Chandra Shekhar Sabapathy, Kanaga |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Tabanifar, Bahareh Moorthy, Anbalagan Tsai, Heng Hang Kannan, Srinivasaraghavan Verma, Chandra Shekhar Sabapathy, Kanaga |
| author_sort | Tabanifar, Bahareh |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T03:03:44Z |
| format | Journal Article |
| id | ntu-10356/171372 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T03:03:44Z |
| publishDate | 2023 |
| record_format | dspace |
| spelling | ntu-10356/1713722023-10-23T15:32:06Z JNK mediates cell death by promoting the ubiquitination of the apurinic/apyrimidinic endonuclease APE1 Tabanifar, Bahareh Moorthy, Anbalagan Tsai, Heng Hang Kannan, Srinivasaraghavan Verma, Chandra Shekhar Sabapathy, Kanaga School of Biological Sciences Bioinformatics Institute, A*STAR National Cancer Centre, Singapore Department of Biological Sciences, NUS Science::Biological sciences Apoptosis 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 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. Agency for Science, Technology and Research (A*STAR) National Medical Research Council (NMRC) Published version This research was supported by the National Medical Research Council Singapore (NMRC/ CBRG/0009/2013) and the NCC Cancer Fund (to K.S.). B.T. was partially supported by the Duke-NUS Medical School Khoo Postdoctoral Fellowship Award. S.K. and C.S.V. are supported by A*STAR/BMRC/NSCC Singapore. 2023-10-23T06:04:27Z 2023-10-23T06:04:27Z 2023 Journal Article Tabanifar, B., Moorthy, A., Tsai, H. H., Kannan, S., Verma, C. S. & Sabapathy, K. (2023). JNK mediates cell death by promoting the ubiquitination of the apurinic/apyrimidinic endonuclease APE1. Cell Reports, 42(9), 113123-. https://dx.doi.org/10.1016/j.celrep.2023.113123 2211-1247 https://hdl.handle.net/10356/171372 10.1016/j.celrep.2023.113123 37703179 2-s2.0-85170671816 9 42 113123 en NMRC/ CBRG/0009/2013 Cell Reports © 2023 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). application/pdf |
| spellingShingle | Science::Biological sciences Apoptosis APE1 Tabanifar, Bahareh Moorthy, Anbalagan Tsai, Heng Hang Kannan, Srinivasaraghavan Verma, Chandra Shekhar Sabapathy, Kanaga JNK mediates cell death by promoting the ubiquitination of the apurinic/apyrimidinic endonuclease APE1 |
| title | JNK mediates cell death by promoting the ubiquitination of the apurinic/apyrimidinic endonuclease APE1 |
| title_full | JNK mediates cell death by promoting the ubiquitination of the apurinic/apyrimidinic endonuclease APE1 |
| title_fullStr | JNK mediates cell death by promoting the ubiquitination of the apurinic/apyrimidinic endonuclease APE1 |
| title_full_unstemmed | JNK mediates cell death by promoting the ubiquitination of the apurinic/apyrimidinic endonuclease APE1 |
| title_short | JNK mediates cell death by promoting the ubiquitination of the apurinic/apyrimidinic endonuclease APE1 |
| title_sort | jnk mediates cell death by promoting the ubiquitination of the apurinic apyrimidinic endonuclease ape1 |
| topic | Science::Biological sciences Apoptosis APE1 |
| url | https://hdl.handle.net/10356/171372 |
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