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bioRxiv · 10.1101/407429

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

Kamata, H.·Kanamoto, M.·Tsuchiya, Y.·Nakao, Y.·Suzuki, T.·Motohashi, H.·Yamamoto, M.
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Abstract

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.

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Kamata, H., Kanamoto, M., Tsuchiya, Y., Nakao, Y., Suzuki, T., Motohashi, H., Yamamoto, M.. 2018-09-03. Structural instability of IκB kinase β promotes autophagic degradation through enhancement of Keap1 binding. https://doi.org/10.1101/407429

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