tetano
Editor, Senior Moderator
J Virol
. 2024 Mar 6:e0156523.
doi: 10.1128/jvi.01565-23. Online ahead of print. The PKA-CREB1 axis regulates coronavirus proliferation by viral helicase nsp13 association
Tong Zheng[SUP] 1 [/SUP], Beilei Shen[SUP] 2 [/SUP], Yu Bai[SUP] 3 [/SUP], Entao Li[SUP] 2 4 [/SUP], Xun Zhang[SUP] 3 [/SUP], Yong Hu[SUP] 1 [/SUP], Ting Gao[SUP] 1 [/SUP], Qincai Dong[SUP] 1 [/SUP], Lin Zhu[SUP] 1 [/SUP], Rui Jin[SUP] 1 [/SUP], Hui Shi[SUP] 1 [/SUP], Hainan Liu[SUP] 1 [/SUP], Yuwei Gao[SUP] 2 [/SUP], Xuan Liu[SUP] 1 [/SUP], Cheng Cao[SUP] 1 [/SUP]
Affiliations
The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed a worldwide threat in the past 3 years. Although it has been widely and intensively investigated, the mechanism underlying the coronavirus-host interaction requires further elucidation, which may contribute to the development of new antiviral strategies. Here, we demonstrated that the host cAMP-responsive element-binding protein (CREB1) interacts with the non-structural protein 13 (nsp13) of SARS-CoV-2, a conserved helicase for coronavirus replication, both in cells and in lung tissues subjected to SARS-CoV-2 infection. The ATPase and helicase activity of viral nsp13 were shown to be potentiated by CREB1 association, as well as by Protein kinase A (PKA)-mediated CREB1 activation. SARS-CoV-2 replication is significantly suppressed by PKA Cα, cAMP-activated protein kinase catalytic subunit alpha (PRKACA), and CREB1 knockdown or inhibition. Consistently, the CREB1 inhibitor 666-15 has shown significant antiviral effects against both the WIV04 strain and the Omicron strain of the SARS-CoV-2. Our findings indicate that the PKA-CREB1 signaling axis may serve as a novel therapeutic target against coronavirus infection.
Importance: In this study, we provide solid evidence that host transcription factor cAMP-responsive element-binding protein (CREB1) interacts directly with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) helicase non-structural protein 13 (nsp13) and potentiate its ATPase and helicase activity. And by live SARS-CoV-2 virus infection, the inhibition of CREB1 dramatically impairs SARS-CoV-2 replication in vivo. Notably, the IC50 of CREB1 inhibitor 666-15 is comparable to that of remdesivir. These results may extend to all highly pathogenic coronaviruses due to the conserved nsp13 sequences in the virus.
Keywords: CREB1; SARS-CoV-2; helicase; nsp13; viral replication.
. 2024 Mar 6:e0156523.
doi: 10.1128/jvi.01565-23. Online ahead of print. The PKA-CREB1 axis regulates coronavirus proliferation by viral helicase nsp13 association
Tong Zheng[SUP] 1 [/SUP], Beilei Shen[SUP] 2 [/SUP], Yu Bai[SUP] 3 [/SUP], Entao Li[SUP] 2 4 [/SUP], Xun Zhang[SUP] 3 [/SUP], Yong Hu[SUP] 1 [/SUP], Ting Gao[SUP] 1 [/SUP], Qincai Dong[SUP] 1 [/SUP], Lin Zhu[SUP] 1 [/SUP], Rui Jin[SUP] 1 [/SUP], Hui Shi[SUP] 1 [/SUP], Hainan Liu[SUP] 1 [/SUP], Yuwei Gao[SUP] 2 [/SUP], Xuan Liu[SUP] 1 [/SUP], Cheng Cao[SUP] 1 [/SUP]
Affiliations
- PMID: 38445884
- DOI: 10.1128/jvi.01565-23
The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed a worldwide threat in the past 3 years. Although it has been widely and intensively investigated, the mechanism underlying the coronavirus-host interaction requires further elucidation, which may contribute to the development of new antiviral strategies. Here, we demonstrated that the host cAMP-responsive element-binding protein (CREB1) interacts with the non-structural protein 13 (nsp13) of SARS-CoV-2, a conserved helicase for coronavirus replication, both in cells and in lung tissues subjected to SARS-CoV-2 infection. The ATPase and helicase activity of viral nsp13 were shown to be potentiated by CREB1 association, as well as by Protein kinase A (PKA)-mediated CREB1 activation. SARS-CoV-2 replication is significantly suppressed by PKA Cα, cAMP-activated protein kinase catalytic subunit alpha (PRKACA), and CREB1 knockdown or inhibition. Consistently, the CREB1 inhibitor 666-15 has shown significant antiviral effects against both the WIV04 strain and the Omicron strain of the SARS-CoV-2. Our findings indicate that the PKA-CREB1 signaling axis may serve as a novel therapeutic target against coronavirus infection.
Importance: In this study, we provide solid evidence that host transcription factor cAMP-responsive element-binding protein (CREB1) interacts directly with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) helicase non-structural protein 13 (nsp13) and potentiate its ATPase and helicase activity. And by live SARS-CoV-2 virus infection, the inhibition of CREB1 dramatically impairs SARS-CoV-2 replication in vivo. Notably, the IC50 of CREB1 inhibitor 666-15 is comparable to that of remdesivir. These results may extend to all highly pathogenic coronaviruses due to the conserved nsp13 sequences in the virus.
Keywords: CREB1; SARS-CoV-2; helicase; nsp13; viral replication.