The Cullin 3 substrate adaptor KLHL20 mediates DAPK ubiquitination to control interferon responses
Resource
EMBO JOURNAL, 29(10), 1748-1761
Journal
The EMBO Journal
Pages
1748-1761
Date Issued
2010
Date
2010
Author(s)
Lee, Yu-Ru
Yuan, Wei-Chien
Ho, Hsuan-Chung
Chen, Chun-Hau
Shih, Hsiu-Ming
Chen, Ruey-Hwa
Abstract
Death-associated protein kinase (DAPK) was identified as a mediator of interferon (IFN)-induced cell death. How IFN controls DAPK activation remains largely unknown. Here, we identify the BTB-Kelch protein KLHL20 as a negative regulator of DAPK. KLHL20 binds DAPK and Cullin 3 (Cul3) via its Kelch-repeat domain and BTB domain, respectively. The KLHL20-Cul3-ROC1 E3 ligase complex promotes DAPK polyubiquitination, thereby inducing the proteasomal degradation of DAPK. Accordingly, depletion of KLHL20 diminishes DAPK ubiquitination and degradation. The KLHL20-mediated DAPK ubiquitination is suppressed in cells receiving IFN-α or IFN-γ, which induces an enrichment/sequestration of KLHL20 in the PML nuclear bodies, thereby separating KLHL20 from DAPK. Consequently, IFN triggers the stabilization of DAPK. This mechanism of DAPK stabilization is crucial for determining IFN responsiveness of tumor cells and contributes to IFN-induced autophagy. This study identifies KLHL20-Cul3-ROC1 as an E3 ligase for DAPK ubiquitination and reveals a regulatory mechanism of DAPK, through blocking its accessibility to this E3 ligase, in IFN-induced apoptotic and autophagic death. Our findings may be relevant to the problem of IFN resistance in cancer therapy. ? 2010 European Molecular Biology Organization.
Subjects
BTB domain; Cullin 3; DAPK; Interferon; PML nuclear bodies
SDGs
Other Subjects
adaptor protein; alpha interferon; cullin; cullin 3; death associated protein kinase; gamma interferon; interferon; proteasome; protein KLHL20; ubiquitin protein ligase E3; unclassified drug; apoptosis; article; autophagy; cell nucleus inclusion body; complex formation; controlled study; human; human cell; immune response; priority journal; protein degradation; protein domain; protein protein interaction; protein stability; regulatory mechanism; tumor cell; ubiquitination; Animals; Apoptosis Regulatory Proteins; Autophagy; Calcium-Calmodulin-Dependent Protein Kinases; Carrier Proteins; Cullin Proteins; Gene Expression Regulation; Hela Cells; Humans; Interferons; Mice; Models, Biological; Neoplasms; NIH 3T3 Cells; Phenotype; Ubiquitin; Ubiquitin-Protein Ligases
Type
journal article
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