PKA-CREB1 Axis Regulates Coronavirus Proliferation By Viral Helicase Nsp13 Association
Nikhil Prasad Fact checked by:Thailand Medical News Team Mar 12, 2024 1 month, 2 weeks, 1 day, 6 hours, 10 minutes ago
COVID-19 News: The relentless global battle against the COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spurred extensive research efforts to comprehend the intricate interactions between the virus and its host. While vaccines and antiviral drugs have been instrumental in disease control, uncovering the detailed mechanisms of virus-host interactions remains crucial for developing innovative antiviral strategies. This
COVID-19 News report delves into a groundbreaking study conducted by researchers from the Beijing Institute of Biotechnology-China, Chinese Academy of Agricultural Sciences, and Anhui University, revealing the pivotal role of the PKA-CREB1 signaling axis in regulating SARS-CoV-2 proliferation through its association with the viral helicase, non-structural protein 13 (nsp13).
Graphical view of the mechanism by which the PKA-CREB1 axis regulated viral replication through the nsp13:CREB1 interaction. (1) Following entry and uncoating, the RNA genome of SARS-CoV-2 is translated to generate a viral replication complex from ORF1a/b (including nsp12 and nsp13). (2) The helicase nsp13 directly interacts with the host transcription factor CREB1 at the site of viral replication and transcription, resulting in enhanced helicase and ATPase activities of nsp13. (3) PKA Cα-mediated phosphorylation of CREB1 enhanced its promoting effect on nsp13 helicase activity. (4) Viral nsp13 binds CREB1, resulting in the accumulation of CREB1 in the cytoplasm and preventing it from entering the nucleus. (5) Whether the reduction of CREB1 in the nucleus will affect the life activities of the host and its relationship with the pathogenic mechanism of the virus remains to be studied.
Understanding Coronaviruses and the Urgency of Mechanistic Insight
Coronaviruses (CoVs) have long been known to cause respiratory and intestinal infections in animals and humans. The recent emergence of SARS-CoV-2 has brought unprecedented challenges, leading to a global pandemic with profound consequences for public health and the global economy. Despite the development of vaccines and antiviral drugs, a comprehensive understanding of the virus-host interaction mechanisms is imperative for devising effective therapeutic interventions.
CoVs possess a positive-sense single-stranded RNA genome and encode four structural proteins: spike protein (S), envelope protein (E), membrane glycoprotein (M), and nucleocapsid protein (N). The non-structural proteins, particularly nsp13, play a crucial role in the CoV replication-transcription complex by unwinding double-stranded nucleic acid helices into single-stranded nucleic acids. Nsp13's high conservation across CoVs underscores its significance, sharing 99.8% identity in amino acid sequences between SARS-CoV and SARS-CoV-2.
PKA-CREB1 Signaling Axis: A New Player in the SARS-CoV-2 Interactome
The study sheds light
on the previously unexplored role of the protein kinase A (PKA)-CREB1 signaling axis in the context of SARS-CoV-2 infection. PKA, a cAMP-dependent serine/threonine kinase, has been implicated in various viral infections, including Ebola virus, HIV-1, hepatitis B virus, Zika virus, and adenovirus. However, its involvement in CoV infection and pathogenesis had remained elusive until now.
The research reveals a direct interaction between SARS-CoV-2 nsp13 and PKA catalytic subunit alpha (PRKACA) and CREB1. The association of CREB1 with nsp13 was demonstrated both in cultured cells and in lung tissues infected with SARS-CoV-2. Intriguingly, the study elucidates that the PKA-CREB1 axis enhances the ATPase and helicase activities of viral nsp13. This potentiation, mediated by CREB1 association and PRKACA-mediated CREB1 activation, ultimately facilitates SARS-CoV-2 replication.
Inhibition of PKA-CREB1: A Novel Antiviral Strategy
To assess the significance of PKA-CREB1 in SARS-CoV-2 replication, the researchers employed various experimental approaches, including knockdowns, inhibitory treatments, and a trVLP system. Notably, both PKA Cα, PRKACA, and CREB1 knockdown or inhibition resulted in a substantial suppression of SARS-CoV-2 replication. The CREB1 inhibitor 666-15 emerged as a promising antiviral agent, exhibiting significant efficacy against multiple SARS-CoV-2 strains, including the WIV04 and Omicron variants.
Furthermore, the study explored the subcellular localization of the nsp13-PKA-CREB1 complex, revealing colocalization in the endoplasmic reticulum region. This observation suggests that nsp13 might hijack CREB1, facilitating its transport into the membrane structure formed by the endoplasmic reticulum, a critical site for SARS-CoV-2 transcription and replication.
Implications for Broad-Spectrum Antiviral Therapeutics
The findings presented in this study have far-reaching implications for the development of broad-spectrum antiviral therapeutics against highly pathogenic coronaviruses. By targeting the conserved nsp13 sequences, the PKA-CREB1 signaling axis emerges as a promising therapeutic target. This is particularly relevant given the high conservation of nsp13 across different CoVs.
The study provides not only mechanistic insights into the interaction between host and virus but also offers a novel avenue for therapeutic development. The CREB1 inhibitor 666-15, exhibiting efficacy comparable to the FDA-approved antiviral drug remdesivir, showcases the potential of targeting host proteins as a strategy with broader-spectrum activity against diverse viral strains.
Conclusion
The COVID-19 pandemic has underscored the need for innovative antiviral strategies. The study conducted by researchers from the Beijing Institute of Biotechnology-China, Chinese Academy of Agricultural Sciences, and Anhui University unravels the intricate interplay between the PKA-CREB1 signaling axis and SARS-CoV-2 nsp13. The discovery of this interaction's role in enhancing viral helicase activity and replication opens new possibilities for therapeutic interventions.
As we navigate the ongoing challenges posed by SARS-CoV-2 and potential future coronaviruses, understanding the virus-host interaction mechanisms becomes paramount. The PKA-CREB1 signaling axis, identified in this study, not only provides a deeper understanding of viral replication but also unveils a novel therapeutic target with the potential for broad-spectrum antiviral efficacy. The CREB1 inhibitor 666-15, demonstrating significant antiviral effects, paves the way for further research and development of host-targeted therapeutics against COVID-19 and related diseases.
The study findings were published in the peer reviewed Journal of Virology.
https://journals.asm.org/doi/10.1128/jvi.01565-23
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