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Effect of depletion of KEAP1 on gene expression after LPS and IFN-γ stimulation of THP-1 derived macrophages

ABSTRACT: To investigate the function of KEAP1 in the regulation of macrophage pro-inflammatory polarization, we established a KEAP1 deletion cell line using CRISPR Cas9 technology. We then performed gene expression profiling analysis using data obtained from RNA-seq of 10 different samples at two time points.

ORGANISM(S): Homo sapiens

PROVIDER: GSE216352 | GEO | 2023/08/03

REPOSITORIES: GEO

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Effect of depletion of KEAP1 on gene expression after LPS and IFN-γ stimulation of THP-1 derived macrophages

Project description:Effect of depletion of KEAP1 on gene expression after LPS and IFN-γ stimulation of THP-1 derived macrophages

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Keap1 is an endogenous dCas9 suppressor inhibiting CRISPRa and CRISPRi efficiency

Project description:As a potent and accurate genome-editing tool, CRISPR-Cas9 has been widely used in biomedical research and evaluated as gene therapy in treating human diseases. Although distinct engineered Cas9s, dCas9s and additional endonucleases have been identified, as these bacterial enzymes do not naturally express in mammalian cells, whether and how bacterial Cas9 proteins are regulated by mammalian hosts remains poorly understood. Here, we identified Keap1 as an endogenous E3 ligase that targets Cas9/dCas9/Fanzor1 for ubiquitination and degradation. Cas9-“ETGE” mutants evading Keap1 recognition displayed enhanced gene editing ability in cells. dCas9-“ETGE” mutants displayed extended protein half-life on chromatin, leading to significantly improved CRISPa and CRISPRi efficacy. Cas9 binding to Keap1 also inactivate Keap1 function via competing with Keap1 substrates or binding partners, while engineered Cas9 mutants showed less perturbation. Thus, our study reveals a mammalian specific Cas9 regulation and provides new Cas9 designs not only with enhanced gene regulatory capacity but also with minimal effects on disrupting endogenous Keap1 signaling.

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Effect of KEAP1 knockout and CDDO-2P-Im Treatment in ARH-77 Cells

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Expression data from Keap1 overexpression and Nrf2 knockdown lung cancer cell

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Project description:Cancer-derived loss-of-function mutations in the KEAP1 tumor suppressor gene stabilize the NRF2 transcription factor, resulting in a pro-survival gene expression program that alters cellular metabolism and neutralizes oxidative stress. In a previous study of KEAP1 mutations observed in lung cancer, we classified 40% of the mutations as ‘superbinders’ (superbinders). These mutants bind and ubiquitylate NRF2 but do not promote NRF2 degradation. Here, we further investigated the molecular mechanism(s) driving the superbinder phenotype. BioID-based quantitative proteomic analysis of the R320Q and R470C superbinder mutations revealed increased co-complexed NRF2 without significant alteration to other KEAP1-associated proteins, including CUL3, VCP, and several ubiquitin receptors within the proteasome lid. Dynamic simulation modeling and limited proteolysis analyses suggest that superbinder mutations stabilize residues in KEAP1 that contact NRF2. In cells, KEAP1 R320Q and R470C mutants co-localize with NRF2, p62/SQSTM1 and polyubiquitin in spherical clusters that rapidly fuse and dissolve; KEAP1-NRF2 localization to these clusters requires p62. Expression of R320Q and R470C in lung cancer cells provided resistance to the reactive oxygen species-inducing drug bleomycin. We present a model wherein superbinder mutations alter the conformational dynamics of the KEAP1-NRF2 complex to alter the cycling of KEAP1 between open and closed conformations, thus inhibiting NRF2 degradation.

2018-11-07 | PXD008411 | Pride

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