p62/SQSTM1 accumulation due to degradation inhibition and transcriptional activation plays a critical role in silica nanoparticle-induced airway inflammation via NF-κB activation

Wu, Yifan; Yang, Jin; Sun, Tianyu; Zhu, Piaoyu; Li, Jinlong; Wang, Xiaoke; Jiang, Junkang; Chen, Gang; Zhao, Xinyuan

doi:10.1186/s12951-020-00634-1

Cited by 26 publications

(11 citation statements)

References 46 publications

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“…They found a significantly higher accumulation of SQSTM1 in smokers as compared to nonsmokers, and an increased severity of COPD. Wu et al ( 2020 ) found that the accumulation of SQSTM1 plays a critical role in airway inflammation induced by nanoparticles.…”

Section: Resultsmentioning

confidence: 99%

Targeting CK2 mediated signaling to impair/tackle SARS-CoV-2 infection: a computational biology approach

Miranda

Bringas

Fernández-de-Cossío

et al. 2021

Mol Med

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Background Similarities in the hijacking mechanisms used by SARS-CoV-2 and several types of cancer, suggest the repurposing of cancer drugs to treat Covid-19. CK2 kinase antagonists have been proposed for cancer treatment. A recent study in cells infected with SARS-CoV-2 found a significant CK2 kinase activity, and the use of a CK2 inhibitor showed antiviral responses. CIGB-300, originally designed as an anticancer peptide, is an antagonist of CK2 kinase activity that binds to the CK2 phospho-acceptor sites. Recent preliminary results show the antiviral activity of CIGB-300 using a surrogate model of coronavirus. Here we present a computational biology study that provides evidence, at the molecular level, of how CIGB-300 may interfere with the SARS-CoV-2 life cycle within infected human cells. Methods Sequence analyses and data from phosphorylation studies were combined to predict infection-induced molecular mechanisms that can be interfered by CIGB-300. Next, we integrated data from multi-omics studies and data focusing on the antagonistic effect on the CK2 kinase activity of CIGB-300. A combination of network and functional enrichment analyses was used. Results Firstly, from the SARS-CoV studies, we inferred the potential incidence of CIGB-300 in SARS-CoV-2 interference on the immune response. Afterwards, from the analysis of multiple omics data, we proposed the action of CIGB-300 from the early stages of viral infections perturbing the virus hijacking of RNA splicing machinery. We also predicted the interference of CIGB-300 in virus-host interactions that are responsible for the high infectivity and the particular immune response to SARS-CoV-2 infection. Furthermore, we provided evidence of how CIGB-300 may participate in the attenuation of phenotypes related to muscle, bleeding, coagulation and respiratory disorders. Conclusions Our computational analysis proposes putative molecular mechanisms that support the antiviral activity of CIGB-300.

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Section: Resultsmentioning

confidence: 99%

Targeting CK2 mediated signaling to impair/tackle SARS-CoV-2 infection: a computational biology approach

Miranda

Bringas

Fernández-de-Cossío

et al. 2021

Mol Med

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show abstract

“…They found a significant higher accumulation of SQSTM1 in smokers as compared to nonsmokers, and an increased severity of COPD. Wu et al [42] found that the accumulation of SQSTM1 plays a critical role in airway inflammation induced by nanoparticles.…”

Section: Resultsmentioning

confidence: 99%

CIGB-300 synthetic peptide, an antagonist of CK2 kinase activity, as a treatment for Covid-19. A computational biology approach

Miranda

Bringas

Fernández-de-Cossío

et al. 2021

Preprint

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Drug repositioning became the first choice for treating Covid-19 patients due to the urgent need to deal with the pandemic. Similarities in the hijacking mechanisms used by SARS-CoV-2 and several type of cancer, suggest the repurposing of cancer drugs to treat Covid-19. CK2 kinase antagonists have been proposed for the treatment of cancer. A recent study in cells infected with SARS-CoV-2 virus found a significant CK2 kinase activity, and the use of a CK2 inhibitor showed antiviral responses. CIGB-300, originally designed as an anticancer peptide, is an antagonist of CK2 kinase activity that binds to CK2 phospho-acceptor sites. Recent preliminary results show an antiviral activity of CIGB-300 versus a surrogate model of coronavirus. Here we present a computational biology study that provides evidences at the molecular level of how CIGB-300 might interfere with SARS-CoV-2 life cycle inside infected human cells. First, from SARS-CoV studies, we infer the potential incidence of CIGB-300 in SARS-CoV-2 interference on immune response. Next, from the analysis of multiple Omics data, we propose the action of CIGB-300 since early stage of viral infections perturbing the virus hijacking of RNA splicing machinery. It was also predicted the interference of CIGB-300 in virus-host interactions responsible for the high infectivity and the particular immune response to SARS-CoV-2 infection. Further, we provide evidences of CIGB-300 attenuation of phenotypes related to muscle, bleeding, coagulation and respiratory disorders.

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“…3C). Several TFs such as activating transcription factor 3 (ATF3), kruppel like factor 5 (KLF5), and specificity protein 1 (SP1) and the previously reported TF of p62, nuclear factor E2-related factor (Nrf2), (13,14) were identified to stimulate the p62-Luc reporter activity as well as the mRNA level of p62 co-transfected with LINC01134, among which SP1 was the most vigorous stimulators in both luciferase and quantitative PCR assays, indicating that SP1 was the most possible TF responsible for LINC01134 up-regulation of p62 transcription (Supporting Fig. S4A,B).…”

Section: Linc01134 Up-regulates P62 Expression By Enhancing the Recru...mentioning

confidence: 99%

LSD1‐Demethylated LINC01134 Confers Oxaliplatin Resistance Through SP1‐Induced p62 Transcription in HCC

Kang

et al. 2021

Hepatology

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Background and Aims Oxaliplatin (OXA) is one of the most common chemotherapeutics in advanced hepatocellular carcinoma (HCC), the resistance of which poses a big challenge. Long noncoding RNAs (lncRNAs) play vital roles in chemoresistance. Therefore, elucidating the underlying mechanisms and identifying predictive lncRNAs for OXA resistance is needed urgently. Methods RNA sequencing (RNA‐seq) and fluorescence in situ hybridization (FISH) were used to investigate the OXA‐resistant (OXA‐R) lncRNAs. Survival analysis was performed to determine the clinical significance of homo sapiens long intergenic non‐protein‐coding RNA 1134 (LINC01134) and p62 expression. Luciferase, RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), and chromatin isolation by RNA purification (ChIRP) assays were used to explore the mechanisms by which LINC01134 regulates p62 expression. The effects of LINC01134/SP1/p62 axis on OXA resistance were evaluated using cell viability, apoptosis, and mitochondrial function and morphology analysis. Xenografts were used to estimate the in vivo regulation of OXA resistance by LINC01134/SP1/p62 axis. ChIP, cell viability, and xenograft assays were used to identify the demethylase for LINC01134 up‐regulation in OXA resistance. Results LINC01134 was identified as one of the most up‐regulated lncRNAs in OXA‐R cells. Higher LINC01134 expression predicted poorer OXA therapeutic efficacy. LINC01134 activates anti‐oxidative pathway through p62 by recruiting transcription factor SP1 to the p62 promoter. The LINC01134/SP1/p62 axis regulates OXA resistance by altering cell viability, apoptosis, and mitochondrial homeostasis both in vitro and in vivo. Furthermore, the demethylase, lysine specific demethylase 1 (LSD1) was responsible for LINC01134 up‐regulation in OXA‐R cells. In patients with HCC, LINC01134 expression was positively correlated with p62 and LSD1 expressions, whereas SP1 expression positively correlated with p62 expression. Conclusions LSD1/LINC01134/SP1/p62 axis is critical for OXA resistance in HCC. Evaluating LINC01134 expression in HCC will be effective in predicting OXA efficacy. In treatment‐naive patients, targeting the LINC01134/SP1/p62 axis may be a promising strategy to overcome OXA chemoresistance.

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p62/SQSTM1 accumulation due to degradation inhibition and transcriptional activation plays a critical role in silica nanoparticle-induced airway inflammation via NF-κB activation

Cited by 26 publications

References 46 publications

Targeting CK2 mediated signaling to impair/tackle SARS-CoV-2 infection: a computational biology approach

Targeting CK2 mediated signaling to impair/tackle SARS-CoV-2 infection: a computational biology approach

CIGB-300 synthetic peptide, an antagonist of CK2 kinase activity, as a treatment for Covid-19. A computational biology approach

LSD1‐Demethylated LINC01134 Confers Oxaliplatin Resistance Through SP1‐Induced p62 Transcription in HCC

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