Protein Kinase C Inhibitors Reduce SARS-CoV-2 Replication in Cultured Cells

Huang, Chenghui; Feng, Fan; Shi, Yongxia; Li, Wenhui; Wang, Ziqiao; Zhu, Yangyong; Yuan, Shuai; Hu, Dandan; Dai, Jun; Jiang, Qiqi; Zhang, Rong; Liu, Chao; Zhang, Ping

doi:10.1128/spectrum.01056-22

Cited by 20 publications

(13 citation statements)

References 36 publications

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“…Additionally, the presence of PKCα/β is essential for IBV or N protein-mediated suppression of antiviral gene expression (Fig 9F and Fig 11F) and facilitates IBV infection (Fig 9 D-E). In line with our findings, a recent study has demonstrated that the replication of SARS-CoV-2 is impeded by pan-PKC inhibitors such as Go 6983, Bisindolmaleimide I, Enzastaurin, and Sotrastaurin [75]. This suggests that PKC may play an essential role in facilitating coronavirus infection.…”

Section: Discussionsupporting

confidence: 91%

Coronavirus Nucleocapsid Protein Enhances the binding of p-PKCα to RACK1: Implications for Inhibition of Nucleocytoplasmic Trafficking and Suppression of the Innate Immune Response

Xue,

Chu,

Wang

et al. 2024

Preprint

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The hallmark of coronavirus infection lies in its ability to evade host immune defenses, a process intricately linked to the nuclear entry of transcription factors crucial for initiating the expression of antiviral genes. Central to this evasion strategy is the manipulation of the nucleocytoplasmic trafficking system, which serves as an effective target for the virus to modulate the expression of immune response-related genes. In this investigation, we discovered that infection with the infectious bronchitis virus (IBV) dynamically impedes the nuclear translocation of several transcription factors such as IRF3, STAT1, STAT2, NF-κB p65, and the p38 mitogen-activated protein kinase (MAPK), leading to compromised transcriptional induction of key antiviral genes such as IFNβ, IFITM3, and IL-8. Further examination revealed that during the infection process, components of the nuclear pore complex (NPC), particularly FG-Nups (such as NUP62, NUP153, NUP42, and TPR), undergo cytosolic dispersion from the nuclear envelope; NUP62 undergoes phosphorylation, and NUP42 exhibits a mobility shift in size. These observations suggest a disruption in nucleocytoplasmic trafficking. Screening efforts identified the IBV nucleocapsid protein (N) as the agent responsible for the cytoplasmic distribution of FG-Nups, subsequently hindering the nuclear entry of transcription factors and suppressing the expression of antiviral genes. Interactome analysis further revealed that the IBV N protein interacts with the scaffold protein RACK1, facilitating the recruitment of activated protein kinase C alpha (p-PKCα) to RACK1 and relocating the RACK1-PKCα complex to the cytoplasm. These observations are conserved across pan-coronaviruses N proteins. Concurrently, the presence of both RACK1 and PKCα/β proved essential for the phosphorylation and cytoplasmic dispersion of NUP62, the suppression of antiviral cytokine expression, and efficient virus replication. These findings unveil a novel, highly effective, and evolutionarily conserved mechanism.Author summaryCoronaviruses employ diverse strategies to suppress the host innate immune defense. In this study, we uncovered a novel and highly effective strategy utilized by pan-coronaviruses to inhibit the innate immune response. Specifically, we found that the coronavirus N protein facilitates the binding of p-PKCα to RACK1, leading to the phosphorylation of NUP62 and the cytoplasmic redistribution of multiple FG-Nups. This phenomenon is accompanied by the disruption of nuclear translocation of several innate immune response-related transcription factors and suppression of antiviral/pro-inflammatory genes expression. Our research represents the first elucidation of how the N protein targets and impairs NPC function through the promotion of RACK1-PKCα interaction and NUP62 phosphorylation/disassembly. This discovery unveils a novel mechanism employed by pan-coronaviruses to counteract the host immune response.

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Section: Discussionsupporting

confidence: 91%

Coronavirus Nucleocapsid Protein Enhances the binding of p-PKCα to RACK1: Implications for Inhibition of Nucleocytoplasmic Trafficking and Suppression of the Innate Immune Response

Xue,

Chu,

Wang

et al. 2024

Preprint

View full text Add to dashboard Cite

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“…Because many polymorphisms in various PKC genes have been identified and because drugs targeting PKC are under investigation in clinical trials for cancer and other diseases ( Callender et al, 2018 ; Kawano et al, 2021 ; Ma et al, 2010 ), future research should explore whether PKC regulation impacts human susceptibility and the severity of SARS-CoV-2 infection. A recent study reported that PKC inhibitors block the replication of ancestral SARS-CoV-2 on A459/ACE2 expressing cells ( Huang et al, 2022 ). The biological effects of PKC are wide-ranging, and even though most PKC isoenzymes are ubiquitous and many cells can co-express different PKC isoforms, some of them are expressed in a tissue-specific manner ( Blázquez and Saiz, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Discovery of lead natural products for developing pan-SARS-CoV-2 therapeutics

et al. 2023

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“…An in vitro study revealed that bisindolylmaleimide IX, a PKC inhibitor, targets the viral protease 3CLpro 57 . Another study found that several inhibitors of protein kinases C (PKCs) including enzastaurin decrease the replication of SARS-CoV-2 in cultured cells 58 . The evidence above indicates that enzastaurin is a potential therapeutic agent against SARS-CoV-2.…”

Section: Resultsmentioning

confidence: 99%

Integrating population-level and cell-based signatures for drug repositioning

He,

Xu,

Zhou

et al. 2023

Preprint

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Drug repositioning presents a streamlined and cost-efficient way to expand the range of therapeutic possibilities. Furthermore, drugs with genetic evidence are more likely to progress successfully through clinical trials towards FDA approval. Exploiting these developments, single gene-based drug repositioning methods have been implemented, but approaches leveraging the entire spectrum of molecular signatures are critically underexplored. Most multi-gene-based approaches rely on differential gene expression (DGE) analysis, which is prone to identify the molecular consequence of disease and renders causal inference challenging. We propose a framework TReD (Transcriptome-informed Reversal Distance) that integrates population-level disease signatures robust to reverse causality and cell-based drug-induced transcriptome response profiles. TReD embeds the disease signature and drug profile in a high-dimensional normed space, quantifying the reversal potential of candidate drugs in a disease-related cell screen assay. The robustness is ensured by evaluation in additional cell screens. For an application, we implement the framework to identify potential drugs against COVID-19. Taking transcriptome-wide association study (TWAS) results from four relevant tissues and three DGE results as disease features, we identify 37 drugs showing potential reversal roles in at least four of the seven disease signatures. Notably, over 70% (27/37) of the drugs have been linked to COVID-19 from other studies, and among them, eight drugs are supported by ongoing/completed clinical trials. For example, TReD identifies the well-studied JAK1/JAK2 inhibitor baricitinib, the first FDA-approved immunomodulatory treatment for COVID-19. Novel potential candidates, including enzastaurin, a selective inhibitor of PKC-beta which can be activated by SARS-CoV-2, are also identified. In summary, we propose a comprehensive genetics-anchored framework integrating population-level signatures and cell-based screens that can accelerate the search for new therapeutic strategies.

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Protein Kinase C Inhibitors Reduce SARS-CoV-2 Replication in Cultured Cells

Cited by 20 publications

References 36 publications

Coronavirus Nucleocapsid Protein Enhances the binding of p-PKCα to RACK1: Implications for Inhibition of Nucleocytoplasmic Trafficking and Suppression of the Innate Immune Response

Coronavirus Nucleocapsid Protein Enhances the binding of p-PKCα to RACK1: Implications for Inhibition of Nucleocytoplasmic Trafficking and Suppression of the Innate Immune Response

Discovery of lead natural products for developing pan-SARS-CoV-2 therapeutics

Integrating population-level and cell-based signatures for drug repositioning

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