Structural instability of IκB kinase β promotes autophagic degradation through enhancement of Keap1 binding

IKK{beta}, an essential kinase of NF-[kcy]B signaling, is composed of an N-terminal kinase domain (KD) and a C-terminal scaffolding domain, containing a ubiquitin-like domain (ULD). The Hsp90 chaperon has special responsibility for folding of protein kinases including IKK{beta}. Here, we found that Hsp90 inhibition induced IKK{beta} degradation, which is partially mediated by Keap1. Geldanamycin (GA), a Hsp90 inhibitor, enhances association of IKK{beta} with Keap1 through the binding site in KD, and translocates IKK{beta} to detergent-insoluble fractions leading its autophagic degradation. An electrophile tBHQ suppressed Keap1-mediated proteasomal Nrf2 degradation but not autophagic IKK{beta} degradation. Substitution mutation of Leu353 to Ala in the ULD destabilizes IKK{beta}, enhances its association with Keap1, translocates it to detergent-insoluble fractions, and causes its autophagic degradation. These results suggest that Keap1 is involved in the degradation of structural destabilized IKK{beta} and negative regulation of NF-[kcy]B under proteotoxic stress.