RRC ID 55887
Author Kanamoto M, Tsuchiya Y, Nakao Y, Suzuki T, Motohashi H, Yamamoto M, Kamata H.
Title Structural instability of IκB kinase β promotes autophagic degradation through enhancement of Keap1 binding.
Journal PLoS One
Abstract IKKβ, an essential kinase of NF-κB 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 IKKβ. Here, we found that Hsp90 inhibition induced IKKβ degradation, which is partially mediated by Keap1. Geldanamycin (GA), a Hsp90 inhibitor, enhances association of IKKβ with Keap1 through the binding site in KD, and translocates IKKβ to detergent-insoluble fractions leading to its autophagic degradation. An electrophile tBHQ suppressed Keap1-mediated proteasomal Nrf2 degradation but not autophagic IKKβ degradation. Substitution mutation of Leu353 to Ala in the ULD destabilizes IKKβ, 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 IKKβ and negative regulation of NF-κB under proteotoxic stress.
Volume 13(11)
Pages e0203978
Published 2018-11-30
DOI 10.1371/journal.pone.0203978
PII PONE-D-18-25233
PMID 30500824
PMC PMC6267955
MeSH Amino Acid Substitution Animals Autophagy* HEK293 Cells HSP90 Heat-Shock Proteins / genetics HSP90 Heat-Shock Proteins / metabolism Humans I-kappa B Kinase / genetics I-kappa B Kinase / metabolism* Kelch-Like ECH-Associated Protein 1 / genetics Kelch-Like ECH-Associated Protein 1 / metabolism* Mice Mice, Knockout Mutation, Missense NF-kappa B / genetics NF-kappa B / metabolism Protein Domains Protein Folding Protein Transport / genetics Proteolysis*
IF 2.776
Times Cited 0
Human and Animal Cells 293(RCB1637)