Selective degradation of IKKα by autophagy is essential for arsenite-induced cancer cell apoptosis

Cell Death Dis. 2020 Apr 7;11(4):222. doi: 10.1038/s41419-020-2420-5.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Arsenites / toxicity*
  • Autophagy / physiology
  • Checkpoint Kinase 1 / metabolism
  • Down-Regulation
  • Hep G2 Cells
  • Humans
  • I-kappa B Kinase / metabolism*
  • Membrane Proteins / metabolism
  • Neoplasms / chemically induced*
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Signal Transduction / drug effects
  • Transfection
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Arsenites
  • DRAM1 protein, human
  • Membrane Proteins
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • CHUK protein, human
  • I-kappa B Kinase
  • arsenite