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

Two catalytic subunits of the IKK complex, IKKalpha and IKKbeta, trigger NF-kappaB activation as well as NF-kappaB-independent signaling events under both physiological and pathological conditions. Here we identified the NF-kappaB-unrelated cytoprotective function of IKKalpha 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 IKKalpha kinase activity. Furthermore, IKKalpha triggered p53/DRAM1-dependent autophagy by inducing CHK1 activation and CHK1/p53 interaction. Interestingly, after provoking autophagy, IKKalpha could be specifically recognized by the autophagic machinery via directly binding with LC3B, resulting in selective degradation of IKKalpha by autophagy. Unexpectedly, the selectivity of autophagic sequestration towards IKKalpha was mediated by novel mechanism independent of the classical LC3-interacting regions (LIRs) within IKKalpha, while C-terminal arm of LIR was involved in mediating IKKalpha/LC3B interaction. Taken together, we conclude that IKKalpha attenuates arsenite-induced apoptosis by inducing p53-dependent autophagy, and then selective feedback degradation of IKKalpha by autophagy contributes to the cytotoxic response induced by arsenite.