Selective degradation of IKKα by autophagy is essential for arsenite-induced cancer cell apoptosis
| Autor: | Mengnan Ding, Qixing Tan, Rui Jin, Lun Song, Huan Xu, Yongliang Hu, Changyuan Wei, Shuxian Zou, Meiru Hu, Hongli Wang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Cancer Research
Arsenites Immunology Down-Regulation Apoptosis Transfection Article Cellular and Molecular Neuroscience Transactivation Mediator Downregulation and upregulation Neoplasms Macroautophagy Autophagy Cytotoxic T cell Humans lcsh:QH573-671 Kinase activity lcsh:Cytology Chemistry Membrane Proteins Cell Biology Hep G2 Cells Cell biology I-kappa B Kinase Checkpoint Kinase 1 Tumor Suppressor Protein p53 Function (biology) Signal Transduction |
| Zdroj: | Cell Death & Disease Cell Death and Disease, Vol 11, Iss 4, Pp 1-15 (2020) |
| ISSN: | 2041-4889 |
| Popis: | Two catalytic subunits of the IKK complex, IKKα and IKKβ, trigger NF-κB activation as well as NF-κB-independent signaling events under both physiological and pathological conditions. Here we identified the NF-κB-unrelated cytoprotective function of IKKα in promoting autophagy by triggering p53 transactivation and upregulation of its downstream autophagic mediator, DRAM1, in the arsenite-treated hepatoma cells, which responses depended on IKKα kinase activity. Furthermore, IKKα triggered p53/DRAM1-dependent autophagy by inducing CHK1 activation and CHK1/p53 interaction. Interestingly, after provoking autophagy, IKKα could be specifically recognized by the autophagic machinery via directly binding with LC3B, resulting in selective degradation of IKKα by autophagy. Unexpectedly, the selectivity of autophagic sequestration towards IKKα was mediated by novel mechanism independent of the classical LC3-interacting regions (LIRs) within IKKα, while C-terminal arm of LIR was involved in mediating IKKα/LC3B interaction. Taken together, we conclude that IKKα attenuates arsenite-induced apoptosis by inducing p53-dependent autophagy, and then selective feedback degradation of IKKα by autophagy contributes to the cytotoxic response induced by arsenite. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|