Viral E Protein Neutralizes BET Protein-Mediated Post-Entry Antagonism of SARS-CoV-2

Chen, Irene P.; Longbotham, James E.; McMahon, Sarah; Suryawanshi, Rahul K.; Carlson-Stevermer, Jared; Gupta, Meghna; Zhang, Meng Yao; Soveg, Frank; Hayashi, Jennifer M.; Taha, Taha Y.; Lam, Victor; Li, Yang; Yu, Zanlin; Titus, Erron W.; Diallo, Amy; Oki, Jennifer; Holden, Kevin; Krogan, Nevan J.; Fujimori, Danica Galonić; Ott, Melanie

doi:10.1101/2021.11.14.468537

Cited by 3 publications

(2 citation statements)

References 55 publications

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“…Moreover, BRD4 displays direct antiviral properties, including inhibition of HIV Tat antigen, hence viruses must neutralize this protein to thrive ( Wang et al, 2020 ; Alamer et al, 2021 ; Xu X. et al, 2021 ; Table 1 ). Indeed, several viruses, including HIV and SARS-CoV-2 have developed the ability to usurp BRD4, overcoming nutritional immunity ( Chen I. P. et al, 2021 ). For example, the E (envelope) protein of SARS-CoV-2 virus inhibits BRD4, neutralizing the function of this epigenetic reader ( Gordon et al, 2020 ).…”

Section: The Brd4/mir-29 Compensatory Systemmentioning

confidence: 99%

Bromodomains in Human-Immunodeficiency Virus-Associated Neurocognitive Disorders: A Model of Ferroptosis-Induced Neurodegeneration

et al. 2022

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Graphical AbstractBoth HIV-1 and cART alter the lysosomes, increasing intracellular iron and the risk of ferroptosis. Dysfunctional lysosomes release the ferroptosis drivers iron, Ca2+ and cathepsin B (catB), promoting neuronal and oligodendrocyte loss, reflected in the white and gray matter pathology. The host responds to lysosomal damage by activating an epigenetic axis comprised of bromodomain 4 (BRD4) and microRNA-29 family (miR-29) that promptly suppresses lysosomal function, lowering ferritinophagy. As there is an inverse relationship between miR-29 and BRD4, HIV-1 inhibition of miR-29, upregulates BRD4, blocking ferritinophagy. The BRD4/miR-29 system also inhibits iron regulatory protein-2 (IRP-2) and augments cystine/glutamate antiporter xCT (SLC7A11), lowering the odds of ferroptosis.

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Section: The Brd4/mir-29 Compensatory Systemmentioning

confidence: 99%

Bromodomains in Human-Immunodeficiency Virus-Associated Neurocognitive Disorders: A Model of Ferroptosis-Induced Neurodegeneration

et al. 2022

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“…Chen et.al. showed that the viral protein E in its acetylated form can directly bind to the second bromodomain of BRD4, and it has evolved to antagonise interferon responses via inhibition of BET proteins (66).…”

Section: Discussionmentioning

confidence: 99%

Discovery of host-directed modulators of virus infection by probing the SARS-CoV-2-host protein-protein interaction network

Ravindran

Wagoner

Athanasiadis

et al. 2022

Preprint

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The ongoing coronavirus disease 2019 (COVID-19) pandemic has highlighted the need to better understand virus-host interactions. We developed a network-based algorithm that expands the SARS-CoV-2-host protein interaction network and identifies host targets that modulate viral infection. To disrupt the SARS-CoV-2 interactome, we systematically probed for potent compounds that selectively target the identified host proteins with high expression in cells relevant to COVID-19. We experimentally tested seven chemical inhibitors of the identified host proteins for modulation of SARS-CoV-2 infection in human cells that express ACE2 and TMPRSS2. Inhibition of the epigenetic regulators bromodomain-containing protein 4 (BRD4) and histone deacetylase 2 (HDAC2), along with ubiquitin specific peptidase (USP10), enhanced SARS-CoV-2 infection. Such proviral effect was observed upon treatment with compounds JQ1, vorinostat, romidepsin, and spautin-1, when measured by cytopathic effect and validated by viral RNA assays, suggesting that HDAC2, BRD4 and USP10 host proteins have antiviral functions. The network-based approach enables systematic identification of host-targets that selectively modulate the SARS-CoV-2 interactome, as well as reveal novel chemical tools to probe virus-host interactions that regulate virus infection.

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From systems to structure — using genetic data to model protein structures

et al. 2022

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Understanding the effects of genetic variation is a fundamental problem in biology that requires methods to analyse both physical and functional consequences of sequence changes at systems-wide and mechanistic scales. To achieve a systems view, protein interaction networks map which proteins physically interact, while genetic interaction networks inform on the phenotypic consequences of perturbing these protein interactions. Until recently, understanding the molecular mechanisms that underlie these interactions often required biophysical methods to determine the structures of the proteins involved. The past decade has seen the emergence of new approaches based on coevolution, deep mutational scanning and genome-scale genetic or chemical–genetic interaction mapping that enable modelling of the structures of individual proteins or protein complexes. Here, we review the emerging use of large-scale genetic datasets and deep learning approaches to model protein structures and their interactions, and discuss the integration of structural data from different sources.

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Viral E Protein Neutralizes BET Protein-Mediated Post-Entry Antagonism of SARS-CoV-2

Cited by 3 publications

References 55 publications

Bromodomains in Human-Immunodeficiency Virus-Associated Neurocognitive Disorders: A Model of Ferroptosis-Induced Neurodegeneration

Bromodomains in Human-Immunodeficiency Virus-Associated Neurocognitive Disorders: A Model of Ferroptosis-Induced Neurodegeneration

Discovery of host-directed modulators of virus infection by probing the SARS-CoV-2-host protein-protein interaction network

From systems to structure — using genetic data to model protein structures

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